Definition
Casein Kinase I (CKI) is a Ser/Thr protein kinase family that has been implicated in regulation of signal transduction1.
Discovery
Casein Kinase activity associated with the endoplasmic reticulum of mammary glands was first characterized in 19742.
Classification
CK I belongs to the kinase family of proteins. It has five isoforms- alpha, beta, gamma, delta and epsilon which are conserved from yeast to humans3.
Structural Characteristics
CK I structure is characterized by nine alpha helices and nine beta strands. The N terminal and C terminal lobes are connected by a single loop4. The cleft lying between the two lobes binds to the nucleotide substrate4. The small N-terminal lobe contains five twisted antiparallel strands, one helix, and the glycine rich sequence motif, Glyl9-Glu-Gly-Ser-Phe-Gly-Val25. The C terminal lobe conisists of four long alpha helices in a antiparallel bundle with a fifth long helix almost perpendicular to the bundle. Overall CK I is rich in Lys and Arg residues4.
Mode of action
Previously phosphorylated substrates are good candidates for secondary phosphorylation by CK I5. It also prefers acidic substrates5.
Functions
CK I is involved in membrane trafficking, circadian rhythm, cell cycle progression, chromosome segregation, apoptosis and cellular differentiation3. Mutations and deregulation of CK1 expression and activity has been linked to various diseases such as Alzheimer's, Parkinson's disease, sleeping disorders and cancer3. It is also involved in Wnt signaling pathway6.
References
1.Gross SD, Anderson RA (1998). Casein kinase I: spatial organization and positioning of a multifunctional protein kinase family. Cell Signal, 10(10), 699-711.
2.Bingham E and Farrel H (1974). Casein kinase from the Golgi apparatus of lactating mammary gland. J. Biol. Chem., 249, 3647-51.
3.Knippschild U, Wolff S, Giamas G, Brockschmidt C, Wittau M, Würl PU, Eismann T, Stöter M (2005). The role of the casein kinase 1 (CK1) family in different signaling pathways linked to cancer development. Onkologie, 28(10), 508-14.
4.Xu RM, Carmel G,Sweet RM, Kuret J and Cheng X (1995). Crystal structure of casein kinase-1, a phosphate-directed protein kinase. EMBO J, 14 (5), 1015-23.
5.Flotow H, Graves PR, Wang AQ, Fiol CJ, Roeske RW, Roach PJ (1990). Phosphate groups as substrate determinants for casein kinase I action. J Biol Chem, 265(24), 14264-9.
6.G. Davidson, W. Wu, J. Shen, J. Bilic, U. Fenger, P. Stannek, A. Glinka and C. Niehrs (2005). Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature, 438, 867-872.
Saturday, July 25, 2009
Circumsporozoite (CS) Protein Sequence
Definition
Circumsporozoite (CS) protein is an antigen present on sporozoite cell surface that is characterized by conserved tandem repeats in their central region1. They are known to be a major target of host immune response1.
Discovery
CS protein was first identified in 1980 when antibodies from fused plasmocytoma cells/murine spleen cells could bind to a protein (now known as CS) on the cell surface of sporozoites2.
Classification
The CS protein belongs to the Thrombospondin-related Protein Family of Apicomplexan Parasites3.
Structural Characteristics
All CS proteins possess a signal sequence at the N-terminus and a hydrophobic sequence at their C-terminus4. In the center is a relatively conserved region of tandem repeats that considerably differs in length, sequence and number depending on the species4. This repetitive region serves as an immunodominant epitope4.
Mode of action
Upon cell contact the sporozoite translocates the CS protein by an unknown mechanism into the cytosol of the cell5. It then spreads throughout the cytosol and binds to cytoplasmic and endoplasmic ribosomes and hence controls protein synthesis in the host cell5.
Functions
CS protein is the major target for host immune response6. The repetitive epitopes of the CS protein are candidates for developing a vaccine against malaria6.
References
1.Schofield L (1990). The circumsporozoite protein of Plasmodium: a mechanism of immune evasion by the malaria parasite? Bull World Health Organ, 68, 66-73.
2.Yoshida N, Nussenzweig RS, Potocnjak P, Nussenzweig V, Aikawa M (1980). Hybridoma produces protective antibodies directed against the sporozoite stage of malaria parasite. Science, 207(4426), 71-3.
3.Naitza S, Spano F, Robson KJH and Crisant A (1998). The Thrombospondin-related Protein Family of Apicomplexan Parasites: The Gears of the Cell Invasion Machinery. Parasitology Today, 14 (12), 479-484.
4.Book: Advances in Parasitology, John R. Baker, R. Mulle, 81-83.
5.Frevert U, Galinski MR, Hügel FU, Allon N, Schreier H, Smulevitch S, Shakibaei M, and Clavijo P (1998). Malaria circumsporozoite protein inhibits protein synthesis in mammalian cells. EMBO J, 17(14), 3816–3826.
6.Del Giudice G, Tougne C, Louis JA, Lambert PH, Bianchi E, Bonelli F, Chiappinelli L, Pessi A (2005). A multiple antigen peptide from the repetitive sequence of the Plasmodium malariae circumsporozoite protein induces a specific antibody response in mice of various H-2 haplotypes. Euro J of Immunol., 20 (7), 1619-1622.
Circumsporozoite (CS) protein is an antigen present on sporozoite cell surface that is characterized by conserved tandem repeats in their central region1. They are known to be a major target of host immune response1.
Discovery
CS protein was first identified in 1980 when antibodies from fused plasmocytoma cells/murine spleen cells could bind to a protein (now known as CS) on the cell surface of sporozoites2.
Classification
The CS protein belongs to the Thrombospondin-related Protein Family of Apicomplexan Parasites3.
Structural Characteristics
All CS proteins possess a signal sequence at the N-terminus and a hydrophobic sequence at their C-terminus4. In the center is a relatively conserved region of tandem repeats that considerably differs in length, sequence and number depending on the species4. This repetitive region serves as an immunodominant epitope4.
Mode of action
Upon cell contact the sporozoite translocates the CS protein by an unknown mechanism into the cytosol of the cell5. It then spreads throughout the cytosol and binds to cytoplasmic and endoplasmic ribosomes and hence controls protein synthesis in the host cell5.
Functions
CS protein is the major target for host immune response6. The repetitive epitopes of the CS protein are candidates for developing a vaccine against malaria6.
References
1.Schofield L (1990). The circumsporozoite protein of Plasmodium: a mechanism of immune evasion by the malaria parasite? Bull World Health Organ, 68, 66-73.
2.Yoshida N, Nussenzweig RS, Potocnjak P, Nussenzweig V, Aikawa M (1980). Hybridoma produces protective antibodies directed against the sporozoite stage of malaria parasite. Science, 207(4426), 71-3.
3.Naitza S, Spano F, Robson KJH and Crisant A (1998). The Thrombospondin-related Protein Family of Apicomplexan Parasites: The Gears of the Cell Invasion Machinery. Parasitology Today, 14 (12), 479-484.
4.Book: Advances in Parasitology, John R. Baker, R. Mulle, 81-83.
5.Frevert U, Galinski MR, Hügel FU, Allon N, Schreier H, Smulevitch S, Shakibaei M, and Clavijo P (1998). Malaria circumsporozoite protein inhibits protein synthesis in mammalian cells. EMBO J, 17(14), 3816–3826.
6.Del Giudice G, Tougne C, Louis JA, Lambert PH, Bianchi E, Bonelli F, Chiappinelli L, Pessi A (2005). A multiple antigen peptide from the repetitive sequence of the Plasmodium malariae circumsporozoite protein induces a specific antibody response in mice of various H-2 haplotypes. Euro J of Immunol., 20 (7), 1619-1622.
Circumsporozoite (CS) Protein Repetitive Sequences
Definition
Circumsporozoite (CS) protein is an antigen present on sporozoite cell surface that is characterized by conserved tandem repeats in their central region1. They are known to be a major target of host immune response1.
Discovery
CS protein was first identified in 1980 when antibodies from fused plasmocytoma cells/murine spleen cells could bind to a protein (now known as CS) on the cell surface of sporozoites2.
Classification
The CS protein belongs to the Thrombospondin-related Protein Family of Apicomplexan parasites3.
Structural Characteristics
All CS proteins possess a signal sequence at the N-terminus and a hydrophobic sequence at their C-terminus4. In the center is a relatively conserved region of tandem repeats that considerably differs in length, sequence and number depending on the species4. This repetitive region serves as an immunodominant epitope4.
Mode of action
Upon cell contact the sporozoite translocates the CS protein by an unknown mechanism into the cytosol of the cell5. It then spreads throughout the cytosol and binds to cytoplasmic and endoplasmic ribosomes and hence controls protein synthesis in the host cell5.
Functions
CS protein is the major target for host immune response6. The repetitive epitopes of the CS protein are candidates for developing a vaccine against malaria6.
References
1.Schofield L (1990). The circumsporozoite protein of Plasmodium: a mechanism of immune evasion by the malaria parasite? Bull World Health Organ, 68, 66-73.
2.Yoshida N, Nussenzweig RS, Potocnjak P, Nussenzweig V, Aikawa M (1980). Hybridoma produces protective antibodies directed against the sporozoite stage of malaria parasite. Science, 207(4426), 71-3.
3.Naitza S, Spano F, Robson KJH and Crisant A (1998). The Thrombospondin-related Protein Family of Apicomplexan Parasites: The Gears of the Cell Invasion Machinery. Parasitology Today, 14 (12), 479-484.
4.Book: Advances in Parasitology, John R. Baker, R. Mulle, 81-83.
5.Frevert U, Galinski MR, Hügel FU, Allon N, Schreier H, Smulevitch S, Shakibaei M, and Clavijo P (1998). Malaria circumsporozoite protein inhibits protein synthesis in mammalian cells. EMBO J, 17(14), 3816–3826.
6.Del Giudice G, Tougne C, Louis JA, Lambert PH, Bianchi E, Bonelli F, Chiappinelli L, Pessi A (2005). A multiple antigen peptide from the repetitive sequence of the Plasmodium malariae circumsporozoite protein induces a specific antibody response in mice of various H-2 haplotypes. Euro J of Immunol., 20 (7), 1619-1622.
Circumsporozoite (CS) protein is an antigen present on sporozoite cell surface that is characterized by conserved tandem repeats in their central region1. They are known to be a major target of host immune response1.
Discovery
CS protein was first identified in 1980 when antibodies from fused plasmocytoma cells/murine spleen cells could bind to a protein (now known as CS) on the cell surface of sporozoites2.
Classification
The CS protein belongs to the Thrombospondin-related Protein Family of Apicomplexan parasites3.
Structural Characteristics
All CS proteins possess a signal sequence at the N-terminus and a hydrophobic sequence at their C-terminus4. In the center is a relatively conserved region of tandem repeats that considerably differs in length, sequence and number depending on the species4. This repetitive region serves as an immunodominant epitope4.
Mode of action
Upon cell contact the sporozoite translocates the CS protein by an unknown mechanism into the cytosol of the cell5. It then spreads throughout the cytosol and binds to cytoplasmic and endoplasmic ribosomes and hence controls protein synthesis in the host cell5.
Functions
CS protein is the major target for host immune response6. The repetitive epitopes of the CS protein are candidates for developing a vaccine against malaria6.
References
1.Schofield L (1990). The circumsporozoite protein of Plasmodium: a mechanism of immune evasion by the malaria parasite? Bull World Health Organ, 68, 66-73.
2.Yoshida N, Nussenzweig RS, Potocnjak P, Nussenzweig V, Aikawa M (1980). Hybridoma produces protective antibodies directed against the sporozoite stage of malaria parasite. Science, 207(4426), 71-3.
3.Naitza S, Spano F, Robson KJH and Crisant A (1998). The Thrombospondin-related Protein Family of Apicomplexan Parasites: The Gears of the Cell Invasion Machinery. Parasitology Today, 14 (12), 479-484.
4.Book: Advances in Parasitology, John R. Baker, R. Mulle, 81-83.
5.Frevert U, Galinski MR, Hügel FU, Allon N, Schreier H, Smulevitch S, Shakibaei M, and Clavijo P (1998). Malaria circumsporozoite protein inhibits protein synthesis in mammalian cells. EMBO J, 17(14), 3816–3826.
6.Del Giudice G, Tougne C, Louis JA, Lambert PH, Bianchi E, Bonelli F, Chiappinelli L, Pessi A (2005). A multiple antigen peptide from the repetitive sequence of the Plasmodium malariae circumsporozoite protein induces a specific antibody response in mice of various H-2 haplotypes. Euro J of Immunol., 20 (7), 1619-1622.
Chorionic Gonadotropin (hCG) Fragments
Definition
Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced during pregnancy1. It is made by the developing embryo soon after conception1. Its role is to prevent the disintegration of the corpus luteum of the ovary and thereby maintain progesterone production that is critical for a pregnancy in humans1.
Discovery
The activity of hCG was first identified in 1927 when it was demonstrated that the blood and urine of pregnant women contained a gonad-stimulating substance that could induce follicular maturation in immature female mice2.
Classification
hCG is a member of glycoprotein hormone family that also includes LH, FSH and TSH3.
Structural Characteristics
hCG is a heterodimer of two subunits - a and b4. a-subunit consists of 92 amino acids and two carbohydrate moieties that are linked to Asn52 and Asn784. The b?-subunit is 145 amino acids long with six carbohydrate moieties attached to Asn13 and Asn304. It is more acidic that the a- subunit4.
Mode of action
hCG acts through the LHCG receptor that upon binding of hCG activates the G protein that is bound to the receptor internally that in turn activates cAMP3. cAMP activates the cAMP-dependent protein kinase that in turn triggers the transcription of several target genes in the nucleus3.
Functions
hCG promotes the maintenance of the corpus luteum during the beginning of pregnancy, causing it to secrete the hormone progesterone that enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus3. Due to its highly-negative charge, hCG may repel the immune cells of the mother, protecting the fetus during the first trimester. It has also been hypothesized that hCG may be a placental link for the development of local maternal immunotolerance5. Because of its similarity to LH, hCG can also be used clinically to induce ovulation in the ovaries as well as testosterone production in the testes3. It also plays a role in cellular differentiation/proliferation and may activate apoptosis6. hCG levels are used as a measure during pregnancy testing3. Human chorionic gonadotropin is extensively used as a parenteral fertility medication3.
References
1.de Medeiros SF, Norman RJ (2009). Human choriogonadotrophin protein core and sugar branches heterogeneity: basic and clinical insights. Hum Reprod Update, 15(1):69-95.
2.Ascheim S and Zondek B (1927). Das Hormon des Hypophysenvorderlappens: testobjekt zum nachweis des hormons. Klin Wochenschr 6,248–252.
3.Stenman UH, Tiitinen A, Alfthan H, Valmu L (2006) The classification, functions and clinical use of different isoforms of HCG. Hum Reprod Update, 12(6):769-84.
4.Albertini A, Ghielmi S and Belloli S (1982). Structure, immunochemical properties and immunoassay of human chorionic gonadotropin. Intl. J. Clin. & Lab. Res., 12(1), 289-298.
5.Kayisli U, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A (2003). Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand system. J. Immunol., 171 (5), 2305–13.
6.Michels KB, Xue F, Colditz GA, Willett WC (2007). Induced and spontaneous abortion and incidence of breast cancer among young women: a prospective cohort study. Arch. Intern. Med., 167 (8): 814–20.
Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced during pregnancy1. It is made by the developing embryo soon after conception1. Its role is to prevent the disintegration of the corpus luteum of the ovary and thereby maintain progesterone production that is critical for a pregnancy in humans1.
Discovery
The activity of hCG was first identified in 1927 when it was demonstrated that the blood and urine of pregnant women contained a gonad-stimulating substance that could induce follicular maturation in immature female mice2.
Classification
hCG is a member of glycoprotein hormone family that also includes LH, FSH and TSH3.
Structural Characteristics
hCG is a heterodimer of two subunits - a and b4. a-subunit consists of 92 amino acids and two carbohydrate moieties that are linked to Asn52 and Asn784. The b?-subunit is 145 amino acids long with six carbohydrate moieties attached to Asn13 and Asn304. It is more acidic that the a- subunit4.
Mode of action
hCG acts through the LHCG receptor that upon binding of hCG activates the G protein that is bound to the receptor internally that in turn activates cAMP3. cAMP activates the cAMP-dependent protein kinase that in turn triggers the transcription of several target genes in the nucleus3.
Functions
hCG promotes the maintenance of the corpus luteum during the beginning of pregnancy, causing it to secrete the hormone progesterone that enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus3. Due to its highly-negative charge, hCG may repel the immune cells of the mother, protecting the fetus during the first trimester. It has also been hypothesized that hCG may be a placental link for the development of local maternal immunotolerance5. Because of its similarity to LH, hCG can also be used clinically to induce ovulation in the ovaries as well as testosterone production in the testes3. It also plays a role in cellular differentiation/proliferation and may activate apoptosis6. hCG levels are used as a measure during pregnancy testing3. Human chorionic gonadotropin is extensively used as a parenteral fertility medication3.
References
1.de Medeiros SF, Norman RJ (2009). Human choriogonadotrophin protein core and sugar branches heterogeneity: basic and clinical insights. Hum Reprod Update, 15(1):69-95.
2.Ascheim S and Zondek B (1927). Das Hormon des Hypophysenvorderlappens: testobjekt zum nachweis des hormons. Klin Wochenschr 6,248–252.
3.Stenman UH, Tiitinen A, Alfthan H, Valmu L (2006) The classification, functions and clinical use of different isoforms of HCG. Hum Reprod Update, 12(6):769-84.
4.Albertini A, Ghielmi S and Belloli S (1982). Structure, immunochemical properties and immunoassay of human chorionic gonadotropin. Intl. J. Clin. & Lab. Res., 12(1), 289-298.
5.Kayisli U, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A (2003). Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand system. J. Immunol., 171 (5), 2305–13.
6.Michels KB, Xue F, Colditz GA, Willett WC (2007). Induced and spontaneous abortion and incidence of breast cancer among young women: a prospective cohort study. Arch. Intern. Med., 167 (8): 814–20.
Cholecystokinin-Pancreozymin Peptides
Definition
Cholecystokinin (CCK), also called pancreozymin, is a peptide hormone in the small intestine that constitutes the classical gut hormone triad together with gastrin and secretin1. CCK is secreted into the blood following ingestion of a meal and plays a critical role in the ingestion, absorption, intestinal motility, satiety signaling, inhibition of gastric acid secretion and digestion of food1.
Discovery
CCK was discovered in 1928 because of its ability to induce gallbladder contraction2.
Classification
CCK is a neuropeptide. It is a family of hormones identified by the number of amino acids, for eg: CCK58 and CCK331.
Structural Characteristics
Prepro-CCK is a115 amino acid peptide that is first cleaved to pro-CCK which in turn results in CCK58, the major processed form of CCK3. CCK58 assumes a helix-turn-helix configuration3.
Mode of action
CCK binds to CCK receptors on the cell membrane that when activated increase the turnover of phosphatidyl inositol which results in the release of intracellular calcium4. The calcium released causes increased enzyme secretion either directly or through activation of protein kinase C4.
Functions
CCK induces the gall bladder to contract and eject bile into the intestine5. It stimulates the acinar cells of the pancreas to release water and ions and stimulates the secretion of a juice rich in pancreatic digestive enzymes5. It is known to induce growth of the exocrine pancreas and to stimulate insulin secretion5. CCK is the most abundant neuropeptide in the human brain where it induces panic attacks that are antagonized by a central cholecystokinin receptor antagonist6. ProCCK is expressed in certain neuroendocrine tumors and sarcomas, and the secretion of CCK is impaired in celiac disease and bulimia nervosa7.
References
1.Fink H, Rex A, Voits M, Voigt JP (1998). Major biological actions of CCK--a critical evaluation of research findings. Exp Brain Res., 123 (1-2), 77–83.
2.Hunt, J. N. (1948). A method for estimating peptic activity in gastric contents. Biochem. J., 42, 104-109.
3.Book: Neuropeptides By Fleur L. Strand, 387-389.
4.Dufresne M, Seva C, Fourmy D (2006). Cholecystokinin and gastrin receptors. Physiol. Rev., 86 (3), 805–47.
5.Chandra R, Liddle RA (2007). Cholecystokinin. Curr Opin Endocrinol Diabetes Obes., 14(1), 63-7.
6.Rehfeld JF, Friis-Hansen L, Goetze JP, Hansen TV (2007). The biology of cholecystokinin and gastrin peptides. Curr Top Med Chem, 7(12), 1154-65.
7.Rehfeld JF (2004). Clinical endocrinology and metabolism. Cholecystokinin. Best Pract Res Clin Endocrinol Metab., 18(4), 569-86.
Cholecystokinin (CCK), also called pancreozymin, is a peptide hormone in the small intestine that constitutes the classical gut hormone triad together with gastrin and secretin1. CCK is secreted into the blood following ingestion of a meal and plays a critical role in the ingestion, absorption, intestinal motility, satiety signaling, inhibition of gastric acid secretion and digestion of food1.
Discovery
CCK was discovered in 1928 because of its ability to induce gallbladder contraction2.
Classification
CCK is a neuropeptide. It is a family of hormones identified by the number of amino acids, for eg: CCK58 and CCK331.
Structural Characteristics
Prepro-CCK is a115 amino acid peptide that is first cleaved to pro-CCK which in turn results in CCK58, the major processed form of CCK3. CCK58 assumes a helix-turn-helix configuration3.
Mode of action
CCK binds to CCK receptors on the cell membrane that when activated increase the turnover of phosphatidyl inositol which results in the release of intracellular calcium4. The calcium released causes increased enzyme secretion either directly or through activation of protein kinase C4.
Functions
CCK induces the gall bladder to contract and eject bile into the intestine5. It stimulates the acinar cells of the pancreas to release water and ions and stimulates the secretion of a juice rich in pancreatic digestive enzymes5. It is known to induce growth of the exocrine pancreas and to stimulate insulin secretion5. CCK is the most abundant neuropeptide in the human brain where it induces panic attacks that are antagonized by a central cholecystokinin receptor antagonist6. ProCCK is expressed in certain neuroendocrine tumors and sarcomas, and the secretion of CCK is impaired in celiac disease and bulimia nervosa7.
References
1.Fink H, Rex A, Voits M, Voigt JP (1998). Major biological actions of CCK--a critical evaluation of research findings. Exp Brain Res., 123 (1-2), 77–83.
2.Hunt, J. N. (1948). A method for estimating peptic activity in gastric contents. Biochem. J., 42, 104-109.
3.Book: Neuropeptides By Fleur L. Strand, 387-389.
4.Dufresne M, Seva C, Fourmy D (2006). Cholecystokinin and gastrin receptors. Physiol. Rev., 86 (3), 805–47.
5.Chandra R, Liddle RA (2007). Cholecystokinin. Curr Opin Endocrinol Diabetes Obes., 14(1), 63-7.
6.Rehfeld JF, Friis-Hansen L, Goetze JP, Hansen TV (2007). The biology of cholecystokinin and gastrin peptides. Curr Top Med Chem, 7(12), 1154-65.
7.Rehfeld JF (2004). Clinical endocrinology and metabolism. Cholecystokinin. Best Pract Res Clin Endocrinol Metab., 18(4), 569-86.
Chlorotoxins
Definition
Chlorotoxin is a 36-amino acid peptide found in the venom of the death-stalker scorpion (Leiurus quinquestriatus) which blocks small-conductance chloride channels1.
Discovery
Chlorotoxin was first purified from scorpion venum in 19931.
Classification
Chlorotoxin belongs to the scorpion toxin superfamily1.
Structural Characteristics
Chlorotoxin is a small positive charged peptide consisting of 30-35 amino acids and 4 disulfide bonds2. Eight cysteine amino acids among its total number of amino acids present in the structure of this peptide are connected with four disulfide bonds2.
Mode of action
Chlorotoxin specifically binds to matrix-metalloproteinase receptor on glioma cells and inhibits it3. It also acts as a ligand for chloride channels and blocks them4.
Functions
As chlorotoxin binds preferentially to glioma cells compared with non-neoplastic cells or normal brain it has has been used to develop new methods for the treatment and diagnosis of several types of cancer5. Chlorotoxin: Cy5.5 bioconjugate has been recently used to demarcate cancer cells from the surrounding normal cells. This gives surgeons a better chance of removing all of the cancerous cells without injuring the surrounding healthy tissue6.
References
1.DeBin JA, Maggio JE, Strichartz GR (1993). Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. Am. J. Physiol., 264 (2 Pt 1), C361–9.
2.Lippens G, Najib J, Wodak SJ, Tartar A (1995). NMR sequential assignments and solution structure of chlorotoxin, a small scorpion toxin that blocks chloride channels. Biochemistry, 34 (1): 13–21.
3.Deshane J, Garner CC, Sontheimer H (2003). Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J. Biol. Chem., 278 (6), 4135–44.
4.DeBin JA, Strichartz GR (1991). Chloride channel inhibition by the venom of the scorpion Leiurus quinquestriatue. Toxicon, 29 (11), 1403–8.
5.Lyons SA, O'Neal J, Sontheimer H (2002). Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia 39 (2), 162–73.
6.Veiseh M, Gabikian P, Bahrami SB, et al (2007). Tumor paint: a chlorotoxin: Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res., 67 (14), 6882–8.
Chlorotoxin is a 36-amino acid peptide found in the venom of the death-stalker scorpion (Leiurus quinquestriatus) which blocks small-conductance chloride channels1.
Discovery
Chlorotoxin was first purified from scorpion venum in 19931.
Classification
Chlorotoxin belongs to the scorpion toxin superfamily1.
Structural Characteristics
Chlorotoxin is a small positive charged peptide consisting of 30-35 amino acids and 4 disulfide bonds2. Eight cysteine amino acids among its total number of amino acids present in the structure of this peptide are connected with four disulfide bonds2.
Mode of action
Chlorotoxin specifically binds to matrix-metalloproteinase receptor on glioma cells and inhibits it3. It also acts as a ligand for chloride channels and blocks them4.
Functions
As chlorotoxin binds preferentially to glioma cells compared with non-neoplastic cells or normal brain it has has been used to develop new methods for the treatment and diagnosis of several types of cancer5. Chlorotoxin: Cy5.5 bioconjugate has been recently used to demarcate cancer cells from the surrounding normal cells. This gives surgeons a better chance of removing all of the cancerous cells without injuring the surrounding healthy tissue6.
References
1.DeBin JA, Maggio JE, Strichartz GR (1993). Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. Am. J. Physiol., 264 (2 Pt 1), C361–9.
2.Lippens G, Najib J, Wodak SJ, Tartar A (1995). NMR sequential assignments and solution structure of chlorotoxin, a small scorpion toxin that blocks chloride channels. Biochemistry, 34 (1): 13–21.
3.Deshane J, Garner CC, Sontheimer H (2003). Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J. Biol. Chem., 278 (6), 4135–44.
4.DeBin JA, Strichartz GR (1991). Chloride channel inhibition by the venom of the scorpion Leiurus quinquestriatue. Toxicon, 29 (11), 1403–8.
5.Lyons SA, O'Neal J, Sontheimer H (2002). Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia 39 (2), 162–73.
6.Veiseh M, Gabikian P, Bahrami SB, et al (2007). Tumor paint: a chlorotoxin: Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res., 67 (14), 6882–8.
Chemotactic Factors
Definition
Chemotactic factors are substances that stimulate cellular locomotion/migration1. Some examples include formyl peptides, chemokines and complement proteins-3a and 5a1.
Discovery
Chemotaxis and chemotactic factors were described as early as 1880’s. The whole process of chemotaxis by chemotactic factors was understood in E.coli in 19742.
Classification
Chemotactic factors are of several groups:
1)Chemokines- b-Thromboglobulin, Chemokines C, CC , CX3C and CXC , Macrophage Inflammatory Proteins
2)Chemotactic Factors, Eosinophil-N-Formylmethionine Leucyl-Phenylalanine
3)Leukocyte Migration-Inhibitory Factors
4)Macrophage Migration-Inhibitory Factors-N-Formylmethionine Leucyl-Phenylalanine
5)Complement proteins- 3a and 5a3.
Structural Characteristics
Structural characteristics of some chemotactic factors are highlighted below:
1)Chemokines have a characteristic composition of beta-sheets and an alpha helix provides expression of sequences required for interaction with the chemokine receptors4.
2)Complement protein C3a is a 77 amino acid peptide with a random coiled C-terminus and a well defined helical N terminus5.
3)Formylated peptides have acylated N-terminal amino group and a strongly hydrophobic C- terminal amino acids6.
Mode of action
In prokaryotic cells, chemical gradients are sensed through multiple transmembrane receptors, called methyl accepting chemotaxis proteins (MCPs), which vary in the molecules that they detect7. These receptors may bind attractants or repellents directly or indirectly through interaction with proteins of periplasmatic space7. The signals from these receptors are transmitted across the plasma membrane into the cytosol, where Che proteins are activated. The Che proteins alter the tumbling frequency, and alter the receptors7.
Eukaryotic cells sense the presence of chemotactic stimuli through the use of 7-transmembrane heterotrimeric G-protein coupled receptors that in turn elicit downstream signaling pathways that ultimately lead to cell migration.7
Functions
Chemoattractants indicate the presence of food to bacteria or if they are repellents they indicate the presence of noxious substances1. Chemoattractants are part of immune system where they attract neutrophils and macrophages to the site of inflammation8. They also function in nervous system where they can guide spinal commissural axons9. Chemokines generated from lymphatic endothelial cells and lymph node cells play a role in the directional migration of dendritic into lymph nodes10. Chemoattractants are also implicated in autoimmune disorders11.
References
1.Kohidai L and Csaba G (1988). Chemotaxis and chemotactic selection induced with cytokines (IL-8, RANTES and TNF alpha) in the unicellular Tetrahymena pyriformis. Cytokine 10, 481–6.
2.Adler J and Tso WW (1974). Decision-making in Bacteria: Chemotactic response of Escherichia Coli to conflicting stimuli. Science 184: 1292–4
3.Book: Chemotaxis, by Eisenbach M, Lengele JW. 253-270.
4.Fernandez E, Lolis E (2002). Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol., 42, 469–99.
5.Nettesheim DG, Edalji RP, Mollison KW, Greer J, and Zuiderweg ER (1988). Secondary structure of complement component C3a anaphylatoxin in solution as determined by NMR spectroscopy: differences between crystal and solution conformations. Proc Natl Acad Sci U S A; 85(14): 5036–5040.
6.Book: Biology of the chemotactic response by J. M. Lackie, Peter Charles Wilkinson, 56-58.
7.Devalaraja MN and Richmond A. Multiple chemotactic factors: fine control or redundancy? Trends in Pharmacological Sciences, 20 (4), 151-156.
8.Haribabu B, Richardson RM, Verghese MW, Barr AJ, Zhelev DV and Snyderma R (2000). Function and regulation of chemoattractant receptors. Immunologic response, 22, 271-279.
9.Galko MJ, Tessier-Lavigne M (2000). Function of an axonal chemoattractant modulated by metalloprotease activity. Science, 289(5483), 1365-7.
10.Wang B, Amerio P, and Sauder DN (1999). Role of cytokines in epidermal Langerhans cell migration. Journal of Leukocyte Biology, 66, 33-39.
11.Tesch GH, Maifert S, Schwarting A, Rollins BJ, Kelley VR (1999). Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice. J Exp Med, 190(12), 1813-24.
Chemotactic factors are substances that stimulate cellular locomotion/migration1. Some examples include formyl peptides, chemokines and complement proteins-3a and 5a1.
Discovery
Chemotaxis and chemotactic factors were described as early as 1880’s. The whole process of chemotaxis by chemotactic factors was understood in E.coli in 19742.
Classification
Chemotactic factors are of several groups:
1)Chemokines- b-Thromboglobulin, Chemokines C, CC , CX3C and CXC , Macrophage Inflammatory Proteins
2)Chemotactic Factors, Eosinophil-N-Formylmethionine Leucyl-Phenylalanine
3)Leukocyte Migration-Inhibitory Factors
4)Macrophage Migration-Inhibitory Factors-N-Formylmethionine Leucyl-Phenylalanine
5)Complement proteins- 3a and 5a3.
Structural Characteristics
Structural characteristics of some chemotactic factors are highlighted below:
1)Chemokines have a characteristic composition of beta-sheets and an alpha helix provides expression of sequences required for interaction with the chemokine receptors4.
2)Complement protein C3a is a 77 amino acid peptide with a random coiled C-terminus and a well defined helical N terminus5.
3)Formylated peptides have acylated N-terminal amino group and a strongly hydrophobic C- terminal amino acids6.
Mode of action
In prokaryotic cells, chemical gradients are sensed through multiple transmembrane receptors, called methyl accepting chemotaxis proteins (MCPs), which vary in the molecules that they detect7. These receptors may bind attractants or repellents directly or indirectly through interaction with proteins of periplasmatic space7. The signals from these receptors are transmitted across the plasma membrane into the cytosol, where Che proteins are activated. The Che proteins alter the tumbling frequency, and alter the receptors7.
Eukaryotic cells sense the presence of chemotactic stimuli through the use of 7-transmembrane heterotrimeric G-protein coupled receptors that in turn elicit downstream signaling pathways that ultimately lead to cell migration.7
Functions
Chemoattractants indicate the presence of food to bacteria or if they are repellents they indicate the presence of noxious substances1. Chemoattractants are part of immune system where they attract neutrophils and macrophages to the site of inflammation8. They also function in nervous system where they can guide spinal commissural axons9. Chemokines generated from lymphatic endothelial cells and lymph node cells play a role in the directional migration of dendritic into lymph nodes10. Chemoattractants are also implicated in autoimmune disorders11.
References
1.Kohidai L and Csaba G (1988). Chemotaxis and chemotactic selection induced with cytokines (IL-8, RANTES and TNF alpha) in the unicellular Tetrahymena pyriformis. Cytokine 10, 481–6.
2.Adler J and Tso WW (1974). Decision-making in Bacteria: Chemotactic response of Escherichia Coli to conflicting stimuli. Science 184: 1292–4
3.Book: Chemotaxis, by Eisenbach M, Lengele JW. 253-270.
4.Fernandez E, Lolis E (2002). Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol., 42, 469–99.
5.Nettesheim DG, Edalji RP, Mollison KW, Greer J, and Zuiderweg ER (1988). Secondary structure of complement component C3a anaphylatoxin in solution as determined by NMR spectroscopy: differences between crystal and solution conformations. Proc Natl Acad Sci U S A; 85(14): 5036–5040.
6.Book: Biology of the chemotactic response by J. M. Lackie, Peter Charles Wilkinson, 56-58.
7.Devalaraja MN and Richmond A. Multiple chemotactic factors: fine control or redundancy? Trends in Pharmacological Sciences, 20 (4), 151-156.
8.Haribabu B, Richardson RM, Verghese MW, Barr AJ, Zhelev DV and Snyderma R (2000). Function and regulation of chemoattractant receptors. Immunologic response, 22, 271-279.
9.Galko MJ, Tessier-Lavigne M (2000). Function of an axonal chemoattractant modulated by metalloprotease activity. Science, 289(5483), 1365-7.
10.Wang B, Amerio P, and Sauder DN (1999). Role of cytokines in epidermal Langerhans cell migration. Journal of Leukocyte Biology, 66, 33-39.
11.Tesch GH, Maifert S, Schwarting A, Rollins BJ, Kelley VR (1999). Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice. J Exp Med, 190(12), 1813-24.
Chemokines
Definition
Chemokines are a family of small cytokines that have the ability to induce chemotaxis in nearby responsive cells1. Proteins are classified as chemokines according to shared structural characteristics such as small size (approximately 8-10 kDa), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape1.
Discovery
Platelet Factor 4 was the first chemokine to be identified in 19742. It was first identified in serum from clotted monkey blood which had the ability of promoting growth of arterial smooth muscles in culture2.
Classification
Chemokine family is classified into four groups: CC, CXC, C and CX3C chemokines. The classification is based on differences in their structural characteristics3.
Structural Characteristics
The CC chemokines have 3-4 cysteines with 2 adjacent cysteines situated near their N terminus3. CXC chemokines also have two cysteines at their N terminus but they are separated by an amino acid3. C chemokines have only one cysteine at their N terminus, the other one being present downstream in their sequence3. The last family of chemokines, CX3C has three amino acids between the N terminal cysteines3.
Mode of action
Chemokines bind to chemokine receptors that activate G proteins which in turn activate the enzyme, Phospholipase C (PLC) 4. PLC cleaves a molecule called phosphatidylinositol (4,5)-bisphosphate into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores4. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor5.
Functions
Chemokines act as a chemoattractant to guide the migration of cells such as directing lymphocytes to the lymph nodes so they can screen for invasion of pathogens by interacting with antigen-presenting cells residing in these tissues. Chemokines also promote angiogenesis or guide cells to tissues that provide specific signals critical for cellular maturation6. Other chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage such as silica or the urate crystals that occur in gout3. Their release is often stimulated by pro-inflammatory cytokines such as interleukin1. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage7. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system7. Inappropraite activation of chemokine network is associated with several diseases such as cardiovascular disease, allergic inflammatory disease, transplantation, neuroinflammation, cancer and HIV-associated disease8.
References
1.Laing K, Secombes C (2004). Chemokines. Dev Comp Immunol., 28 (5), 443–60.
2.Ross R, Glomset J, Kariya B, Harker L (1974). A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A, 71(4), 1207-10.
3.Fernandez E, Lolis E (2002). Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol., 42, 469–99.
4.Lodowski DT, Palczewski K (2009). Chemokine receptors and other G protein-coupled receptors. Curr Opin HIV AIDS, 4(2):88-95.
5.Craig Murdoch and Adam Finn (2000). Chemokine receptors and the role in inflammation and infectious disease. Journal of the American Society of Hematology, 95 (10), 3032–3043.
6.Vindrieux D, Escobar P, Lazennec G (2009). Emerging roles of chemokines in prostate cancer. Endocr Relat Cancer, [Epub ahead of print].
7.Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G (2001). Chemokines and their receptors in the central nervous system. Front Neuroendocrinol, 22(3):147-84.
8.Gerard C & Rollins BJ (2001). Chemokines and disease. Nature Immunology, 2, 108 – 115.
Chemokines are a family of small cytokines that have the ability to induce chemotaxis in nearby responsive cells1. Proteins are classified as chemokines according to shared structural characteristics such as small size (approximately 8-10 kDa), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape1.
Discovery
Platelet Factor 4 was the first chemokine to be identified in 19742. It was first identified in serum from clotted monkey blood which had the ability of promoting growth of arterial smooth muscles in culture2.
Classification
Chemokine family is classified into four groups: CC, CXC, C and CX3C chemokines. The classification is based on differences in their structural characteristics3.
Structural Characteristics
The CC chemokines have 3-4 cysteines with 2 adjacent cysteines situated near their N terminus3. CXC chemokines also have two cysteines at their N terminus but they are separated by an amino acid3. C chemokines have only one cysteine at their N terminus, the other one being present downstream in their sequence3. The last family of chemokines, CX3C has three amino acids between the N terminal cysteines3.
Mode of action
Chemokines bind to chemokine receptors that activate G proteins which in turn activate the enzyme, Phospholipase C (PLC) 4. PLC cleaves a molecule called phosphatidylinositol (4,5)-bisphosphate into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores4. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor5.
Functions
Chemokines act as a chemoattractant to guide the migration of cells such as directing lymphocytes to the lymph nodes so they can screen for invasion of pathogens by interacting with antigen-presenting cells residing in these tissues. Chemokines also promote angiogenesis or guide cells to tissues that provide specific signals critical for cellular maturation6. Other chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage such as silica or the urate crystals that occur in gout3. Their release is often stimulated by pro-inflammatory cytokines such as interleukin1. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage7. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system7. Inappropraite activation of chemokine network is associated with several diseases such as cardiovascular disease, allergic inflammatory disease, transplantation, neuroinflammation, cancer and HIV-associated disease8.
References
1.Laing K, Secombes C (2004). Chemokines. Dev Comp Immunol., 28 (5), 443–60.
2.Ross R, Glomset J, Kariya B, Harker L (1974). A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A, 71(4), 1207-10.
3.Fernandez E, Lolis E (2002). Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol., 42, 469–99.
4.Lodowski DT, Palczewski K (2009). Chemokine receptors and other G protein-coupled receptors. Curr Opin HIV AIDS, 4(2):88-95.
5.Craig Murdoch and Adam Finn (2000). Chemokine receptors and the role in inflammation and infectious disease. Journal of the American Society of Hematology, 95 (10), 3032–3043.
6.Vindrieux D, Escobar P, Lazennec G (2009). Emerging roles of chemokines in prostate cancer. Endocr Relat Cancer, [Epub ahead of print].
7.Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G (2001). Chemokines and their receptors in the central nervous system. Front Neuroendocrinol, 22(3):147-84.
8.Gerard C & Rollins BJ (2001). Chemokines and disease. Nature Immunology, 2, 108 – 115.
Charybdotoxin and Analogs
Definition
Charybdotoxin (CTX) is a 37 amino acid neurotoxin from the venom of the scorpion Leiurus quinquestriatus hebraeus that blocks calcium-activated potassium channels that causes hyperexcitation of the nervous system1.
Discovery
CTX was first identified and partially purified from the venom of the scorpion, Leiurus quinquestriatus hebraeus in 19852. It was found that CTX could reversibly inhibit Ca2+-activated K+ channels of mammalian skeletal muscle2.
Classification
CTX belongs to the charybdotoxin family of potassion channel blocking peptides3.
Structural Characteristics
CTX like other potassium channel blocking peptides has a characteristic fold in its peptide backbone3. It also has three disulphide bridges that hold the three stranded beta-sheet to the two to three turn alpha-helix in place3. The toxicity of CTX depends on the Lys at position 273. Several structural analogs of CTX have been designed4.
Mode of action
CTX blocks potassium channels by binding to a receptor at the opening of the ion conduction pathyway5. It binds both to the open and the closed states5. In addition, the block is enhanced as the ionic strength is lowered6.
Functions
Scorpions such as the deathstalker paralyse their prey by injecting a potent mix of peptide toxins one of which is CTX7. Anti-scorpion venom serum (AScVS) is an effective and safe method of therapy in severe scorpion envenoming syndrome. Compared with other therapies like alpha blockers it has a relatively short recovery period8. CTX is also a good model to study potassium channels7.
References
1.Laurent F, Michel A, Bonnet PA, Chapat JP, Boucard M (1993). Evaluation of the relaxant effects of SCA40, a novel charybdotoxin-sensitive potassium channel opener, in guinea-pig isolated trachealis. Br. J. Pharmacol., 108 (3), 622–6.
2.Miller C, Moczydlowski E, LaTorre R and Phillips M (1985). Charybdotoxin, a protein inhibitor of single Ca2+-activated K+ channels from mammalian skeletal muscle. Nature (Lond), 313, 316-318.
3.Book: Guidebook to protein toxins and their use in cell biology, Rappuoli R, Montecucco C, 143-145.
4.Rauer H, Lanigan MD, Pennington MW, Aiyar J, Ghanshani S, Cahalan MD, Norton RS, Chandy KG (2000). Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca(2+)-activated over voltage-gated K(+) channels. J Biol Chem, 275(2), 1201-8.
5. Naranjo D, Miller C (1996). A strongly interacting pair of residues on the contact surface of charybdotoxin and a Shaker K+ channel. Neuron, 16 (1), 123–30.
6.MacKinnon R, Reinhart PH, White MM (1988). Charybdotoxin block of Shaker K+ channels suggests that different types of K+ channels share common structural features. Neuron, (10): 997–1001.
7.Garcia ML, Knaus HG, Munujos P, Slaughter RS, Kaczorowski GJ (1995). Charybdotoxin and its effects on potassium channels. Am J Physiol., 269(1.1), C1-10.
8. VS, Murthy RK, Deodhar KP (2006). Efficacy of species specific anti-scorpion venom serum (AScVS) against severe, serious scorpion stings (Mesobuthus tamulus concanesis Pocock)—an experience from rural hospital in western Maharashtra. J Assoc Physicians India, 54, 283–7.
Charybdotoxin (CTX) is a 37 amino acid neurotoxin from the venom of the scorpion Leiurus quinquestriatus hebraeus that blocks calcium-activated potassium channels that causes hyperexcitation of the nervous system1.
Discovery
CTX was first identified and partially purified from the venom of the scorpion, Leiurus quinquestriatus hebraeus in 19852. It was found that CTX could reversibly inhibit Ca2+-activated K+ channels of mammalian skeletal muscle2.
Classification
CTX belongs to the charybdotoxin family of potassion channel blocking peptides3.
Structural Characteristics
CTX like other potassium channel blocking peptides has a characteristic fold in its peptide backbone3. It also has three disulphide bridges that hold the three stranded beta-sheet to the two to three turn alpha-helix in place3. The toxicity of CTX depends on the Lys at position 273. Several structural analogs of CTX have been designed4.
Mode of action
CTX blocks potassium channels by binding to a receptor at the opening of the ion conduction pathyway5. It binds both to the open and the closed states5. In addition, the block is enhanced as the ionic strength is lowered6.
Functions
Scorpions such as the deathstalker paralyse their prey by injecting a potent mix of peptide toxins one of which is CTX7. Anti-scorpion venom serum (AScVS) is an effective and safe method of therapy in severe scorpion envenoming syndrome. Compared with other therapies like alpha blockers it has a relatively short recovery period8. CTX is also a good model to study potassium channels7.
References
1.Laurent F, Michel A, Bonnet PA, Chapat JP, Boucard M (1993). Evaluation of the relaxant effects of SCA40, a novel charybdotoxin-sensitive potassium channel opener, in guinea-pig isolated trachealis. Br. J. Pharmacol., 108 (3), 622–6.
2.Miller C, Moczydlowski E, LaTorre R and Phillips M (1985). Charybdotoxin, a protein inhibitor of single Ca2+-activated K+ channels from mammalian skeletal muscle. Nature (Lond), 313, 316-318.
3.Book: Guidebook to protein toxins and their use in cell biology, Rappuoli R, Montecucco C, 143-145.
4.Rauer H, Lanigan MD, Pennington MW, Aiyar J, Ghanshani S, Cahalan MD, Norton RS, Chandy KG (2000). Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca(2+)-activated over voltage-gated K(+) channels. J Biol Chem, 275(2), 1201-8.
5. Naranjo D, Miller C (1996). A strongly interacting pair of residues on the contact surface of charybdotoxin and a Shaker K+ channel. Neuron, 16 (1), 123–30.
6.MacKinnon R, Reinhart PH, White MM (1988). Charybdotoxin block of Shaker K+ channels suggests that different types of K+ channels share common structural features. Neuron, (10): 997–1001.
7.Garcia ML, Knaus HG, Munujos P, Slaughter RS, Kaczorowski GJ (1995). Charybdotoxin and its effects on potassium channels. Am J Physiol., 269(1.1), C1-10.
8. VS, Murthy RK, Deodhar KP (2006). Efficacy of species specific anti-scorpion venom serum (AScVS) against severe, serious scorpion stings (Mesobuthus tamulus concanesis Pocock)—an experience from rural hospital in western Maharashtra. J Assoc Physicians India, 54, 283–7.
Cerebellin and Analogs
Definition
Cerebellin (CER) is a neuromodulatory hexadecapeptide that originates from the precursor protein precerebellin (Cbln1) and modulates synaptic structure formation in the central nervous system1.
Discovery
Cerebellin was first identified and purified from rat cerebellum in 1984 by HPLC techniques2.
Classification
Cerebellin is a neuropeptide generated from the precursor, precerebellin which has four isoforms, Cbln1-41.
Structural Characteristics
Cerebellin is a hexadecamer of primary amino acid sequence NH(2)-Ser-Gly-Ser-Ala-Lys-Val-Ala-Phe-Ser-Ala-Ile-Arg-Ser-Thr-Asn-His- OH3.
Mode of action
One of the functions of cerebellin is to enhance secretory activity of human adrenal gland. It does this by exerting a sizable secretagogue action on both cortex and medulla of human adrenals4. The peptide directly stimulates catecholamine release via the adenylate cyclase/protein kinase A-dependent signaling pathway and the mechanism underlying the adrenocortical stimulatory effect of cerebellin is indirect and probably involves the release of catecholamines, which in turn enhances steroid-hormone secretion4.
Functions
Cerebellin is widely distributed in the central nervous system where it exerts neuromodulatory functions such as synaptic structure formation4. It is also expressed in the peripheral tissues such as pancreas and adrenal glands where it regulates catecholamine secretion4.
References
1.Strowski MZ, Kaczmarek P, Mergler S, Wiedenmann B, Domin D, Szwajkowski P, Wojciechowicz T, Skrzypski M, Szczepankiewicz D, Szkudelski T, Rucinski M, Malendowicz LK, Nowak KW (2009). Insulinostatic activity of cerebellin - Evidence from in vivo and in vitro studies in rats. Regul Pept, EPub ahead of print.
2.Slemmon JR, Blacher R, Danho W, Hemstead JL, Morgan JI (1984). Isolation and sequencing of two cerebellum-specific peptides. Proc Natl Acad Sci USA, 81:6866-6870.
3.Urade Y, Oberdick J, Molinar-Rode R, Morgan JI (1991). Precerebellin is a cerebellum-specific protein with similarity to the globular domain of complement C1q B chain. Proc Natl Acad Sci U S A, 88(3), 1069-73.
4.Mazzocchi G, Andreis PG, De Caro R, Aragona F, Gottardo L, Nussdorfer GG (1999). Cerebellin enhances in vitro secretory activity of human adrenal gland. J Clin Endocrinol Metab, 84(2), 632-5.
Cerebellin (CER) is a neuromodulatory hexadecapeptide that originates from the precursor protein precerebellin (Cbln1) and modulates synaptic structure formation in the central nervous system1.
Discovery
Cerebellin was first identified and purified from rat cerebellum in 1984 by HPLC techniques2.
Classification
Cerebellin is a neuropeptide generated from the precursor, precerebellin which has four isoforms, Cbln1-41.
Structural Characteristics
Cerebellin is a hexadecamer of primary amino acid sequence NH(2)-Ser-Gly-Ser-Ala-Lys-Val-Ala-Phe-Ser-Ala-Ile-Arg-Ser-Thr-Asn-His- OH3.
Mode of action
One of the functions of cerebellin is to enhance secretory activity of human adrenal gland. It does this by exerting a sizable secretagogue action on both cortex and medulla of human adrenals4. The peptide directly stimulates catecholamine release via the adenylate cyclase/protein kinase A-dependent signaling pathway and the mechanism underlying the adrenocortical stimulatory effect of cerebellin is indirect and probably involves the release of catecholamines, which in turn enhances steroid-hormone secretion4.
Functions
Cerebellin is widely distributed in the central nervous system where it exerts neuromodulatory functions such as synaptic structure formation4. It is also expressed in the peripheral tissues such as pancreas and adrenal glands where it regulates catecholamine secretion4.
References
1.Strowski MZ, Kaczmarek P, Mergler S, Wiedenmann B, Domin D, Szwajkowski P, Wojciechowicz T, Skrzypski M, Szczepankiewicz D, Szkudelski T, Rucinski M, Malendowicz LK, Nowak KW (2009). Insulinostatic activity of cerebellin - Evidence from in vivo and in vitro studies in rats. Regul Pept, EPub ahead of print.
2.Slemmon JR, Blacher R, Danho W, Hemstead JL, Morgan JI (1984). Isolation and sequencing of two cerebellum-specific peptides. Proc Natl Acad Sci USA, 81:6866-6870.
3.Urade Y, Oberdick J, Molinar-Rode R, Morgan JI (1991). Precerebellin is a cerebellum-specific protein with similarity to the globular domain of complement C1q B chain. Proc Natl Acad Sci U S A, 88(3), 1069-73.
4.Mazzocchi G, Andreis PG, De Caro R, Aragona F, Gottardo L, Nussdorfer GG (1999). Cerebellin enhances in vitro secretory activity of human adrenal gland. J Clin Endocrinol Metab, 84(2), 632-5.
Wednesday, July 22, 2009
Ceratotoxin Peptides
Definition
Ceratotoxins are antibacterial peptides produced in the female reproductive accessory glands of the medfly Ceratitis capitata1. Their expression is not affected by bacterial infection, but is enhanced after mating and is modulated by juvenile hormone1.
Discovery
Ceratotoxin peptides were first purified from the secretion of the female reproductive accessory glands of the dipteran insect Ceratitis capitata in 19932.
Classification
Ceratotoxins are antibacterial peptides. Three different ceratotoxins have been purified: Ceratotoxins A, B and C1.
Structural Characteristics
All three ceratotoxins are 29 amino acids in length with a difference in two amino acids at positions 6 and 19. They are heat stable and strongly basic3. They are all amphiphilic in nature with their polar amino acids lying parallel to their alpha-helices3. Their antibacterial nature is attributed to this amphiphilic property3.
Mode of action
Ceratotoxins are effective against both gram negative and gram positive bacteria4. They bind to the cell membrane and form voltage dependent ion channels which are responsible for destroying the bacteria4.
Functions
Ceratotoxins are mainly expressed in an adult female insect5. Their main function is to protect the genital tract from bacterial infections during fertilization5.
References
1.Rosetto M, De Filippis T, Manetti AG, Marchini D, Baldari CT, Dallai R (1997). The genes encoding the antibacterial sex-specific peptides ceratotoxins are clustered in the genome of the medfly Ceratitis capitata, Insect Biochem Mol Biol, 27(12), 1039-46.
2.Marchini D, Giordano PC, Amons R, Bernini LF, Dallai R (1993). Purification and primary structure of ceratotoxin A and B, two antibacterial peptides from the female reproductive accessory glands of the medfly Ceratitis capitata (Insecta:Diptera), Insect Biochem Mol Biol, 23(5), 591-8.
3.Book: Molecular mechanisms of immune responses in insects: Paul T. Brey, Dan Hultmark, 74-80.
4.Marri L, Dallai R, Marchini D (1996). The novel antibacterial peptide ceratotoxin A alters permeability of the inner and outer membrane of Escherichia coli K-12, Curr Microbiol, 33(1):40-3.
5.Rosetto M, Manetti AG, Giordano PC, Marri L, Amons R, Baldari CT, Marchini D, Dallai R (1996). Molecular characterization of ceratotoxin C, a novel antibacterial female-specific peptide of the ceratotoxin family from the medfly Ceratitis capitata, Eur J Biochem, 241(2), 330-7.
Ceratotoxins are antibacterial peptides produced in the female reproductive accessory glands of the medfly Ceratitis capitata1. Their expression is not affected by bacterial infection, but is enhanced after mating and is modulated by juvenile hormone1.
Discovery
Ceratotoxin peptides were first purified from the secretion of the female reproductive accessory glands of the dipteran insect Ceratitis capitata in 19932.
Classification
Ceratotoxins are antibacterial peptides. Three different ceratotoxins have been purified: Ceratotoxins A, B and C1.
Structural Characteristics
All three ceratotoxins are 29 amino acids in length with a difference in two amino acids at positions 6 and 19. They are heat stable and strongly basic3. They are all amphiphilic in nature with their polar amino acids lying parallel to their alpha-helices3. Their antibacterial nature is attributed to this amphiphilic property3.
Mode of action
Ceratotoxins are effective against both gram negative and gram positive bacteria4. They bind to the cell membrane and form voltage dependent ion channels which are responsible for destroying the bacteria4.
Functions
Ceratotoxins are mainly expressed in an adult female insect5. Their main function is to protect the genital tract from bacterial infections during fertilization5.
References
1.Rosetto M, De Filippis T, Manetti AG, Marchini D, Baldari CT, Dallai R (1997). The genes encoding the antibacterial sex-specific peptides ceratotoxins are clustered in the genome of the medfly Ceratitis capitata, Insect Biochem Mol Biol, 27(12), 1039-46.
2.Marchini D, Giordano PC, Amons R, Bernini LF, Dallai R (1993). Purification and primary structure of ceratotoxin A and B, two antibacterial peptides from the female reproductive accessory glands of the medfly Ceratitis capitata (Insecta:Diptera), Insect Biochem Mol Biol, 23(5), 591-8.
3.Book: Molecular mechanisms of immune responses in insects: Paul T. Brey, Dan Hultmark, 74-80.
4.Marri L, Dallai R, Marchini D (1996). The novel antibacterial peptide ceratotoxin A alters permeability of the inner and outer membrane of Escherichia coli K-12, Curr Microbiol, 33(1):40-3.
5.Rosetto M, Manetti AG, Giordano PC, Marri L, Amons R, Baldari CT, Marchini D, Dallai R (1996). Molecular characterization of ceratotoxin C, a novel antibacterial female-specific peptide of the ceratotoxin family from the medfly Ceratitis capitata, Eur J Biochem, 241(2), 330-7.
Cell Permeable/Drug Delivery Peptides
Definition
Cell permeable peptides (CPPs) are carriers with small peptide domains that can freely cross cell membranes. They are mainly used as carriers of proteins and nucleic acids into the cell1.
Discovery
The first CPP was discovered independently by two laboratories in 1988 when it was found that the trans-activating transcriptional activator (Tat) from Human Immunodeficiency Virus 1 (HIV-1) could be efficiently taken up from the surrounding media by numerous cell types in culture2.
Structural Characteristics
CPPs typically have an amino acid composition containing either a high relative abundance of positively charged, cationic amino acids such as lysine or arginine, or have sequences that contain an alternating pattern of polar/charged amino acids and non-polar, hydrophobic amino acids3. Some examples include: TAT peptide-YGRKKRRQRRR, lipid membrane translocating peptide-KKAAAVLLPVLLAAP and Antennapedia leader peptide-KKWKMRRNQFWVKVQRG.
Classification
Numerous CPPs have been identified to date and they belong to a wide variety of protein families. For example, some CPPs are amphipatic protein family members3.
Mode of action
CPPs enter the cell with their carrier by either of three mechanisms: Direct delivery that involves energy independent entry of the CPPs in to the cell4, endocytosis where the cells take up the CPPs by imbibing them with their cell membranes5 and translocation through the formation of transient structures which is yet to be understood6.
Functions
CPPs have found numerous applications in medicine as drug delivery agents in the treatment of different diseases including cancer, virus inhibitors, contrast agents for cell labeling a classical example is Green Fluorescent protein GFP, as MRI contrast agents, quantum dots7. TAT is very effective in delivering drugs in vitro and in vivo and so far a peptide that matches its efficiency has not been found7.
References
1.Wagstaff KM and David JA (2006). Protein Transduction: Cell Penetrating Peptides and Their Therapeutic Applications, Current Medicinal Chemistry, 13 (12), 1371-1387.
2.Feng S and Holland EC (1988). HIV-1 Tat trans-activation requires the loop sequence within Tar. Nature 334, 165–167.
3.Stewart KM, Horton KL, Kelley SO (2008). Cell-penetrating peptides as delivery vehicles for biology and medicine, Org Biomol Chem., 6(13), 2242-55.
4.Luo D, Saltzman WM (2000). Synthetic DNA delivery systems. Nat. Biotechnol, 18, 33-37.
5.Lundberg M., Wikstrom S and Johansson M (2003). Cell surface adherence and endocytosis of protein transduction domains, Mol. Ther., 8, 143–150.
6.Deshayes S, Gerbal-Chaloin S, Morris MC, Aldrian-Herrada G, Charnet P, Divita G (2004). On the mechanism of non-endosomial peptide-mediated cellular delivery of nucleic acids, Biochim. Biophys. Acta, 1667, 141–147.
7.Temsamani J and Vida P (2004). The use of cell-penetrating peptides for drug delivery, Drug Discovery Today, 9 (23), 1012-1019.
Cell permeable peptides (CPPs) are carriers with small peptide domains that can freely cross cell membranes. They are mainly used as carriers of proteins and nucleic acids into the cell1.
Discovery
The first CPP was discovered independently by two laboratories in 1988 when it was found that the trans-activating transcriptional activator (Tat) from Human Immunodeficiency Virus 1 (HIV-1) could be efficiently taken up from the surrounding media by numerous cell types in culture2.
Structural Characteristics
CPPs typically have an amino acid composition containing either a high relative abundance of positively charged, cationic amino acids such as lysine or arginine, or have sequences that contain an alternating pattern of polar/charged amino acids and non-polar, hydrophobic amino acids3. Some examples include: TAT peptide-YGRKKRRQRRR, lipid membrane translocating peptide-KKAAAVLLPVLLAAP and Antennapedia leader peptide-KKWKMRRNQFWVKVQRG.
Classification
Numerous CPPs have been identified to date and they belong to a wide variety of protein families. For example, some CPPs are amphipatic protein family members3.
Mode of action
CPPs enter the cell with their carrier by either of three mechanisms: Direct delivery that involves energy independent entry of the CPPs in to the cell4, endocytosis where the cells take up the CPPs by imbibing them with their cell membranes5 and translocation through the formation of transient structures which is yet to be understood6.
Functions
CPPs have found numerous applications in medicine as drug delivery agents in the treatment of different diseases including cancer, virus inhibitors, contrast agents for cell labeling a classical example is Green Fluorescent protein GFP, as MRI contrast agents, quantum dots7. TAT is very effective in delivering drugs in vitro and in vivo and so far a peptide that matches its efficiency has not been found7.
References
1.Wagstaff KM and David JA (2006). Protein Transduction: Cell Penetrating Peptides and Their Therapeutic Applications, Current Medicinal Chemistry, 13 (12), 1371-1387.
2.Feng S and Holland EC (1988). HIV-1 Tat trans-activation requires the loop sequence within Tar. Nature 334, 165–167.
3.Stewart KM, Horton KL, Kelley SO (2008). Cell-penetrating peptides as delivery vehicles for biology and medicine, Org Biomol Chem., 6(13), 2242-55.
4.Luo D, Saltzman WM (2000). Synthetic DNA delivery systems. Nat. Biotechnol, 18, 33-37.
5.Lundberg M., Wikstrom S and Johansson M (2003). Cell surface adherence and endocytosis of protein transduction domains, Mol. Ther., 8, 143–150.
6.Deshayes S, Gerbal-Chaloin S, Morris MC, Aldrian-Herrada G, Charnet P, Divita G (2004). On the mechanism of non-endosomial peptide-mediated cellular delivery of nucleic acids, Biochim. Biophys. Acta, 1667, 141–147.
7.Temsamani J and Vida P (2004). The use of cell-penetrating peptides for drug delivery, Drug Discovery Today, 9 (23), 1012-1019.
Cell Adhesion Peptides
Definition
Cell adhesion peptides are peptides that promote adhesion of normal and tumor cells and are derived from extracellular matrix glycoproteins such as laminin, fibronectin and collagen1.
Discovery
Synthetic cell adhesion peptides were first derived from laminin. The peptide PA22-2 (CSRARKQAASIKVAVSADR-NH2) derived from laminin was found to function as a cell adhesion molecule which was tested with mouse mast cells1.
Classification
Cell adhesion peptides for the most part are extracellular matrix proteins1.
Structural Characteristics
Numerous cell adhesion peptides have been synthesized to date. Some examples include: RU-1 (LNIVSVNGRHX), RX-1 (DNRIRLQAKXX), GD-1 (KATPMLKMRTSFHGCIK), GD-2 (KEGYKVRLDLNITLEFRTTSK), GD-3 (KNLEISRSTFDLLRNSYGVRK), GD-6 (KQNCLSSRASFRGCVRNLRLSR), HGD-6 (KQKCLRSQTSFRGCLRKLALIK), SGD-6 (CRNRGRCNSSLFQVRSRKLLSA), HSGD-6 (KQCLKSQRSFTRGLCRLKAKIL), AG-1 (KLLISRARKQÁASIK), F17 (LERKYENDQKYLEDKA) and KRGD (VEKRGDREEA). Peptides that are linear and cyclic in nature have been synthesized2.
Mode of action
Cell adhesion peptides can bind to the cell membrane and trigger adhesion of cells3.
Functions
Cell adhesion peptides have known to increase signaling via receptors3. They have been shown to decrease tumor metastasis and growth in experimental animals3. These peptides also induce Ca2+ signaling and modulate platelet activity3.
References
1.Thompson HL, Burbelo PD,Yamada Y,Kleinman HK and Metcalfe DD (1991). Identification of an amino acid sequence in the laminin A chain mediating mast cell attachment and spreading, Immunology, 72, 144-149.
2.Gehlsen KR, Sriramarao P, Furcht LT and Skubitzt APN (1992). A Synthetic Peptide Derived from the Carboxy Terminus of the Laminin A Chain Represents a Binding Site for the a3ß1 Integrin, J Cell Biology,117 (2), 449-459.
3.Book: Proteins analysis and design, Angeletti RH, 222-226.
Cell adhesion peptides are peptides that promote adhesion of normal and tumor cells and are derived from extracellular matrix glycoproteins such as laminin, fibronectin and collagen1.
Discovery
Synthetic cell adhesion peptides were first derived from laminin. The peptide PA22-2 (CSRARKQAASIKVAVSADR-NH2) derived from laminin was found to function as a cell adhesion molecule which was tested with mouse mast cells1.
Classification
Cell adhesion peptides for the most part are extracellular matrix proteins1.
Structural Characteristics
Numerous cell adhesion peptides have been synthesized to date. Some examples include: RU-1 (LNIVSVNGRHX), RX-1 (DNRIRLQAKXX), GD-1 (KATPMLKMRTSFHGCIK), GD-2 (KEGYKVRLDLNITLEFRTTSK), GD-3 (KNLEISRSTFDLLRNSYGVRK), GD-6 (KQNCLSSRASFRGCVRNLRLSR), HGD-6 (KQKCLRSQTSFRGCLRKLALIK), SGD-6 (CRNRGRCNSSLFQVRSRKLLSA), HSGD-6 (KQCLKSQRSFTRGLCRLKAKIL), AG-1 (KLLISRARKQÁASIK), F17 (LERKYENDQKYLEDKA) and KRGD (VEKRGDREEA). Peptides that are linear and cyclic in nature have been synthesized2.
Mode of action
Cell adhesion peptides can bind to the cell membrane and trigger adhesion of cells3.
Functions
Cell adhesion peptides have known to increase signaling via receptors3. They have been shown to decrease tumor metastasis and growth in experimental animals3. These peptides also induce Ca2+ signaling and modulate platelet activity3.
References
1.Thompson HL, Burbelo PD,Yamada Y,Kleinman HK and Metcalfe DD (1991). Identification of an amino acid sequence in the laminin A chain mediating mast cell attachment and spreading, Immunology, 72, 144-149.
2.Gehlsen KR, Sriramarao P, Furcht LT and Skubitzt APN (1992). A Synthetic Peptide Derived from the Carboxy Terminus of the Laminin A Chain Represents a Binding Site for the a3ß1 Integrin, J Cell Biology,117 (2), 449-459.
3.Book: Proteins analysis and design, Angeletti RH, 222-226.
CEF Control Peptides
Definition
The CEF control peptides are 8-12 amino acids in length, with sequences derived from the human Cytomegalovirus, Epstein-Barr Virus and Influenza Virus1 These peptides are used in the stimulation of IFNg release from CD8+ T cells in individuals with defined HLA types1. They are useful as positive control peptides in several cytokine assays such as Elispot.
Discovery
CEF peptides were first selected in 2002 based on their ability to recognize CD8+ T cells1.
Classification
They are derived from epitopes of viruses and hence have antigenic properties1.
Structural Characteristics
CEF peptides are 8-11 amino acids long with sequences: GILGFVFTL (Influenza A, HLA-A2), FMYSDFHFI (Influenza A, HLA-A2), CLGGLLTMV (EBV, HLA-A2), GLCTLVAML (EBV, HLA-A2), NLVPMVATV (HCMV, HLA-A2).
Mode of action
CEF peptides are effective epitopes for CD8+ T cells2. They bind to these cells and trigger the production of IFNg.
Functions
CEF control peptides are used as positive control in Elispot assay that is used to investigate specific immune responses in various diseases including infections, cancer, allergies and autoimmune diseases2. In this case the CEF peptides ensure that the cells under study are active and viable2. Elispot is also useful in the development of vaccines especially for HIV where CEF peptides are used also as controls2.
References
1.Currier JR, Kuta EG, Turk E, Earhart LB, Loomis-Price L, Janetzki S, Ferrari G, Birx DL, Cox JH (2002). A panel of MHC class I restricted viral peptides for use as a quality control for vaccine trial ELISPOT assays, J Immunol Methods, 260, 157-172.
2.Gazagne A, Claret E, Wijdenes J, Yssel H, Bousquet F, Levy E, Vielh P, Scotte F, Goupil T, Fridman WH, Tartour E (2003). A Fluorospot assay to detect single T lymphocytes simultaneously producing multiple cytokines, J Immunol Methods, 283(1-2), 91-98.
The CEF control peptides are 8-12 amino acids in length, with sequences derived from the human Cytomegalovirus, Epstein-Barr Virus and Influenza Virus1 These peptides are used in the stimulation of IFNg release from CD8+ T cells in individuals with defined HLA types1. They are useful as positive control peptides in several cytokine assays such as Elispot.
Discovery
CEF peptides were first selected in 2002 based on their ability to recognize CD8+ T cells1.
Classification
They are derived from epitopes of viruses and hence have antigenic properties1.
Structural Characteristics
CEF peptides are 8-11 amino acids long with sequences: GILGFVFTL (Influenza A, HLA-A2), FMYSDFHFI (Influenza A, HLA-A2), CLGGLLTMV (EBV, HLA-A2), GLCTLVAML (EBV, HLA-A2), NLVPMVATV (HCMV, HLA-A2).
Mode of action
CEF peptides are effective epitopes for CD8+ T cells2. They bind to these cells and trigger the production of IFNg.
Functions
CEF control peptides are used as positive control in Elispot assay that is used to investigate specific immune responses in various diseases including infections, cancer, allergies and autoimmune diseases2. In this case the CEF peptides ensure that the cells under study are active and viable2. Elispot is also useful in the development of vaccines especially for HIV where CEF peptides are used also as controls2.
References
1.Currier JR, Kuta EG, Turk E, Earhart LB, Loomis-Price L, Janetzki S, Ferrari G, Birx DL, Cox JH (2002). A panel of MHC class I restricted viral peptides for use as a quality control for vaccine trial ELISPOT assays, J Immunol Methods, 260, 157-172.
2.Gazagne A, Claret E, Wijdenes J, Yssel H, Bousquet F, Levy E, Vielh P, Scotte F, Goupil T, Fridman WH, Tartour E (2003). A Fluorospot assay to detect single T lymphocytes simultaneously producing multiple cytokines, J Immunol Methods, 283(1-2), 91-98.
Cecropin Peptides
Definition
Cercopins are antimicrobial peptides that are part of immune response of silkworm1.
Discovery
Cercopins were first isolated from the silkworm Hyalophora cecropia in 19812.
Classification
Cercopins are of three types, A, B and C which range from 35-38 amino acids in length1.
Structural Characteristics
Cercopin has a helix bend helix motif. Its N-terminus is positively charged and amphipatic in nature1. The C terminus is less charged and hydrophobic1. The hinge between the helices is formed by amino acids Gly 23 and Pro 241.
Mode of action
The amino terminal helix binds to the negative charged head groups on the cell membrane and the hydrophobic residues of the C terminus insert into the membrane core3. Then application of a positive potential pushes the NH2 terminal into the membrane to form pores thus killing the microorganism3.
Functions
Cercopins apart from killing bacteria permeabilize liposomes1. In vitro they are effective against plant pathogenic bacteria1.
References
1.Durell SR, Raghunathan G, Guy HR (1992). Modeling the ion channel structure of cecropin, Biophys J, 63(6), 1623-31.
2.Steiner H, Hultmark D, Engström A, Bennich H, Boman HG (1981). Sequence and specificity of two antibacterial proteins involved in insect immunity, Nature, 292(5820), 246-8.
3.Vaara M and Vaara T (1994). Ability of Cecropin B To Penetrate the Enterobacterial
Outer Membrane, Antimicrobial agents and Chemotherapy,38, 2498-2501.
Cercopins are antimicrobial peptides that are part of immune response of silkworm1.
Discovery
Cercopins were first isolated from the silkworm Hyalophora cecropia in 19812.
Classification
Cercopins are of three types, A, B and C which range from 35-38 amino acids in length1.
Structural Characteristics
Cercopin has a helix bend helix motif. Its N-terminus is positively charged and amphipatic in nature1. The C terminus is less charged and hydrophobic1. The hinge between the helices is formed by amino acids Gly 23 and Pro 241.
Mode of action
The amino terminal helix binds to the negative charged head groups on the cell membrane and the hydrophobic residues of the C terminus insert into the membrane core3. Then application of a positive potential pushes the NH2 terminal into the membrane to form pores thus killing the microorganism3.
Functions
Cercopins apart from killing bacteria permeabilize liposomes1. In vitro they are effective against plant pathogenic bacteria1.
References
1.Durell SR, Raghunathan G, Guy HR (1992). Modeling the ion channel structure of cecropin, Biophys J, 63(6), 1623-31.
2.Steiner H, Hultmark D, Engström A, Bennich H, Boman HG (1981). Sequence and specificity of two antibacterial proteins involved in insect immunity, Nature, 292(5820), 246-8.
3.Vaara M and Vaara T (1994). Ability of Cecropin B To Penetrate the Enterobacterial
Outer Membrane, Antimicrobial agents and Chemotherapy,38, 2498-2501.
Caerulein and Analogs
Definition
Caerulein is a decapeptide obtained from the skin of an Australian amphibian1. It stimulates gastric, biliary and pancreatic secretion and is used as a diagnostic tool in pancreatic malfunctions1.
Discovery
Caerulein was first isolated from the skin of the frog, Hyla caerulea based on the ability of its preparation to stimulate secretion of gastric and pancreatic juices from other experimental animals1,2.
Classification
Caerulein is very similar to cholecystokinin which belongs to gastrin-type family of hormones3.
Structural Characteristics
Caerulein is a decapeptide with the sequence Pyr-Gln-Asp-Tyr(SO3H)-Thr-Gly-Trp-Met-Asp-Phe-NH23. The tyrosine sulphate residue is critical for its biological activity4. Caerulein analogs have related structure to caerulein but their functional potencies vary. Some of the analogs of caerulein include Caerulein 2.1, 3.1, 4.1 (all containing Met) and 2.2, 3.2 and 4.2 (all containing Phe)4.
Mode of action
Caerulein exerts its functions by binding to two types of receptors, CCK1 and CCK2. CCK1 receptor binding directly results in smooth muscle contraction4. Caerulein binds to CCK2 receptors on pancreatic delta cells and triggers the secretion of pancreatic juice. Specifically, it stimulates the hydrolysis of phosphatidylinositol bisphosphate to form inositol trisphosphate and diacylglycerol5. The released inositol trisphosphate could function as a second messenger to mobilize Ca2+ from an intracellular store which in turn stimulates exocytosis5.
Functions
Caerulein produces several behavioral effects in mammals such as inhibition of food and water intake, changes in mood, analgesia, sedation and antipsychotic effects6. Caerulein also stimulates the secretion of pancreatic, bile and gastric juices1.
References
1.Anastasi A, Erspamer V & Endean R (1967). Isolation and structure of caerulein, an active decapeptide from the skin of Hyla caerulea. Experientia, 23, 699-700.
2.Anastasi A, Erspamer V & Endean R (1968). Isolation and amino acid sequence of caerulein, the active decapeptide of the skin of Hyla caerulea. Arch. Biochem. Biophys., 125, 57-68.
3.Caro GD, Endean R, Erspamer V and Roseghini M (1968). Occurrence of Caerulein in extracts of the skin of Hyla caerulia and other Australian hylids. Br. J. Pharmac. Chemother, 33, 48-58.
4.Book: Handbook of Biologically active peptides by Abba J Kastin, Pg 285.
5.Roberto B, Tullio P and Claes BW (1986). Caerulein and carbamoylcholine stimulate pancreatic amylase release at resting cytosolic free Ca2+. Biochem. J., 235, 139-143.
6.Zetler G (1985). Caerulein and its analogues: neuropharmacological properties. Peptides, 6, Suppl 3, 33-46.
Caerulein is a decapeptide obtained from the skin of an Australian amphibian1. It stimulates gastric, biliary and pancreatic secretion and is used as a diagnostic tool in pancreatic malfunctions1.
Discovery
Caerulein was first isolated from the skin of the frog, Hyla caerulea based on the ability of its preparation to stimulate secretion of gastric and pancreatic juices from other experimental animals1,2.
Classification
Caerulein is very similar to cholecystokinin which belongs to gastrin-type family of hormones3.
Structural Characteristics
Caerulein is a decapeptide with the sequence Pyr-Gln-Asp-Tyr(SO3H)-Thr-Gly-Trp-Met-Asp-Phe-NH23. The tyrosine sulphate residue is critical for its biological activity4. Caerulein analogs have related structure to caerulein but their functional potencies vary. Some of the analogs of caerulein include Caerulein 2.1, 3.1, 4.1 (all containing Met) and 2.2, 3.2 and 4.2 (all containing Phe)4.
Mode of action
Caerulein exerts its functions by binding to two types of receptors, CCK1 and CCK2. CCK1 receptor binding directly results in smooth muscle contraction4. Caerulein binds to CCK2 receptors on pancreatic delta cells and triggers the secretion of pancreatic juice. Specifically, it stimulates the hydrolysis of phosphatidylinositol bisphosphate to form inositol trisphosphate and diacylglycerol5. The released inositol trisphosphate could function as a second messenger to mobilize Ca2+ from an intracellular store which in turn stimulates exocytosis5.
Functions
Caerulein produces several behavioral effects in mammals such as inhibition of food and water intake, changes in mood, analgesia, sedation and antipsychotic effects6. Caerulein also stimulates the secretion of pancreatic, bile and gastric juices1.
References
1.Anastasi A, Erspamer V & Endean R (1967). Isolation and structure of caerulein, an active decapeptide from the skin of Hyla caerulea. Experientia, 23, 699-700.
2.Anastasi A, Erspamer V & Endean R (1968). Isolation and amino acid sequence of caerulein, the active decapeptide of the skin of Hyla caerulea. Arch. Biochem. Biophys., 125, 57-68.
3.Caro GD, Endean R, Erspamer V and Roseghini M (1968). Occurrence of Caerulein in extracts of the skin of Hyla caerulia and other Australian hylids. Br. J. Pharmac. Chemother, 33, 48-58.
4.Book: Handbook of Biologically active peptides by Abba J Kastin, Pg 285.
5.Roberto B, Tullio P and Claes BW (1986). Caerulein and carbamoylcholine stimulate pancreatic amylase release at resting cytosolic free Ca2+. Biochem. J., 235, 139-143.
6.Zetler G (1985). Caerulein and its analogues: neuropharmacological properties. Peptides, 6, Suppl 3, 33-46.
C5a-Related Peptides
Definition
C5a is the protein fragment released from the complement protein, C5. It is an anaphylotoxin and causes release of histamines from mast cells1.
Discovery
Complement system was first discovered in the 1880’s as a heat liable bactericidal activity componenet in fresh serum2. Later several components of the complement proteins were identified by protein purification techniques3. C5a was originally purified from rat or porcine plasma that was treated with dextran or cobra venom factor4.
Classification
C3a, C4a and C5a serum proteins of the complement system are all anaphylotoxins5.
Structural Characteristics
In humans, C5a contains 74 amino acids. The molecule is composed of four helices and loops connecting the helices. On the N terminus a short 1.5 turn helix is also present1. The longest helix -IV- develops three disulfide bonds with helix II and III. C5a is rapidly metabolised by a serum enzyme, carboxypeptidase B to a 73 amino acid form, C5a des-Arg1.
Mode of action
C5a binds to a receptor protein on the surface of target cells, C5aR or CD88, a member of the G-protein-coupled receptor superfamily of proteins, predicted to have seven transmembrane helical domains of largely hydrophobic amino acid residues6,7. C5a binding to the receptor is a two-stage process: an interaction between basic residues in the helical core of C5a and acidic residues in the extracellular N-terminal domain allows the C-terminus of C5a to bind to residues in the receptor transmembrane domains6,7. The latter interaction leads to receptor activation, and the transduction of the ligand binding signal across the cell plasma membrane to the cytoplasmic G protein Gi type GNAI26,7.
Functions
C5a is an anaphylatoxin, causing the release of histamine from mast cells; C5a des-Arg is a much less potent anaphylatoxin8. Both C5a and C5a des-Arg are effective leukocyte chemoattractants, causing the accumulation of white blood cells, especially neutrophil granulocytes, at sites of complement activation. It activates white blood cells by increasing avidity for white blood cell integrins and upregulating the Lipoxygenase pathway for arachidonic acid metabolism9. C5a is a powerful inflammatory mediator, and seems to be a key factor in the development of pathology of many inflammatory diseases such as sepsis, asthma and cystic fibrosis10. C5a modulates balance between activating versus inhibitory IgG Fc receptors on leukocytes thereby enhances autoimmune response11.
References
1.Monk PN, Scola AM, Madala P, Fairlie DP (2007). Function, structure and therapeutic potential of complement C5a receptors. Brit. J Pharma., 152, 429–48.
2.Buchner H (1889). Uber die bakterientodtende, Wirkunk des zellenfrien Blutserums. Zentralbl Bakteriol., 5, 1-11.
3.Muller-EHJ (1968). Chemistry and reaction mechanisms of complement. Adv Immunol., 8, 1-80.
4.Stegemann H, Vogt W, and Friedberg KD (1964). Hoppe-Seyler’s Z. Physiol. Chem., 337, 269-276.
5.Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J (2009). The role of the anaphylatoxins in health and disease. Mol. Immunol., [EPub ahead of print].
6.Gerard NP, Gerard C (1991). The chemotactic receptor for human C5a anaphylatoxin. Nature, 349, 614.
7.Gerard C, Gerard NP (1994). C5A anaphylatoxin and its seven transmembrane-segment receptor. Annu Rev Immunol., 12, 775.
8.Schulman ES, Post TJ, Henson PM and Giclas PC (1998). Differential effects of the complement peptides, C5a and C5a des Arg on human basophil and lung mast cell histamine release. J. Clin. Invest., 81(3), 918-923.
9.Mamoru K, Noriyuki S, Yukio T, Hiro-o K, Takeshi K, Tony E. H and Masayoshi A (2000). Intratracheal administration of anaphylatoxin C5a potentiates antigen-induced pulmonary reactions through the prolonged production of cysteinyl–leukotrienes. Immunopharmacology, 49 (3), 263-74.
10.Guo RF, Ward PA (2005). Role of C5a in inflammatory responses. Annu Rev Immunol., 23:821-52.
11.Schmidt RE, Gessner (2005). JEFc receptors and their interaction with complement in autoimmunity. Immunol Lett., 100(1), 56-67.
C5a is the protein fragment released from the complement protein, C5. It is an anaphylotoxin and causes release of histamines from mast cells1.
Discovery
Complement system was first discovered in the 1880’s as a heat liable bactericidal activity componenet in fresh serum2. Later several components of the complement proteins were identified by protein purification techniques3. C5a was originally purified from rat or porcine plasma that was treated with dextran or cobra venom factor4.
Classification
C3a, C4a and C5a serum proteins of the complement system are all anaphylotoxins5.
Structural Characteristics
In humans, C5a contains 74 amino acids. The molecule is composed of four helices and loops connecting the helices. On the N terminus a short 1.5 turn helix is also present1. The longest helix -IV- develops three disulfide bonds with helix II and III. C5a is rapidly metabolised by a serum enzyme, carboxypeptidase B to a 73 amino acid form, C5a des-Arg1.
Mode of action
C5a binds to a receptor protein on the surface of target cells, C5aR or CD88, a member of the G-protein-coupled receptor superfamily of proteins, predicted to have seven transmembrane helical domains of largely hydrophobic amino acid residues6,7. C5a binding to the receptor is a two-stage process: an interaction between basic residues in the helical core of C5a and acidic residues in the extracellular N-terminal domain allows the C-terminus of C5a to bind to residues in the receptor transmembrane domains6,7. The latter interaction leads to receptor activation, and the transduction of the ligand binding signal across the cell plasma membrane to the cytoplasmic G protein Gi type GNAI26,7.
Functions
C5a is an anaphylatoxin, causing the release of histamine from mast cells; C5a des-Arg is a much less potent anaphylatoxin8. Both C5a and C5a des-Arg are effective leukocyte chemoattractants, causing the accumulation of white blood cells, especially neutrophil granulocytes, at sites of complement activation. It activates white blood cells by increasing avidity for white blood cell integrins and upregulating the Lipoxygenase pathway for arachidonic acid metabolism9. C5a is a powerful inflammatory mediator, and seems to be a key factor in the development of pathology of many inflammatory diseases such as sepsis, asthma and cystic fibrosis10. C5a modulates balance between activating versus inhibitory IgG Fc receptors on leukocytes thereby enhances autoimmune response11.
References
1.Monk PN, Scola AM, Madala P, Fairlie DP (2007). Function, structure and therapeutic potential of complement C5a receptors. Brit. J Pharma., 152, 429–48.
2.Buchner H (1889). Uber die bakterientodtende, Wirkunk des zellenfrien Blutserums. Zentralbl Bakteriol., 5, 1-11.
3.Muller-EHJ (1968). Chemistry and reaction mechanisms of complement. Adv Immunol., 8, 1-80.
4.Stegemann H, Vogt W, and Friedberg KD (1964). Hoppe-Seyler’s Z. Physiol. Chem., 337, 269-276.
5.Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J (2009). The role of the anaphylatoxins in health and disease. Mol. Immunol., [EPub ahead of print].
6.Gerard NP, Gerard C (1991). The chemotactic receptor for human C5a anaphylatoxin. Nature, 349, 614.
7.Gerard C, Gerard NP (1994). C5A anaphylatoxin and its seven transmembrane-segment receptor. Annu Rev Immunol., 12, 775.
8.Schulman ES, Post TJ, Henson PM and Giclas PC (1998). Differential effects of the complement peptides, C5a and C5a des Arg on human basophil and lung mast cell histamine release. J. Clin. Invest., 81(3), 918-923.
9.Mamoru K, Noriyuki S, Yukio T, Hiro-o K, Takeshi K, Tony E. H and Masayoshi A (2000). Intratracheal administration of anaphylatoxin C5a potentiates antigen-induced pulmonary reactions through the prolonged production of cysteinyl–leukotrienes. Immunopharmacology, 49 (3), 263-74.
10.Guo RF, Ward PA (2005). Role of C5a in inflammatory responses. Annu Rev Immunol., 23:821-52.
11.Schmidt RE, Gessner (2005). JEFc receptors and their interaction with complement in autoimmunity. Immunol Lett., 100(1), 56-67.
C3a and C3d Peptides
Definition
C3a is an anaphylotoxin and a cleavage product of the major complement protein C31. C3d, important for enhancing B cell responses is produced by cleavage of C3b which is also another product of C31.
Discovery
Complement system was first discovered in the 1880’s as a heat liable bactericidal activity componenet in fresh serum2. Later several components of the complement proteins were identified by protein purification techniques3. C3 and C3d were first isolated from the waste of industrially produced albumin in 19604.
Classification
C3a, C4a and C5a serum proteins of the complement system are all anaphylotoxins5. C3d belongs to the class of antigen binding proteins6.
Structural Characteristics
C3a is a 77 amino acid peptide with a random coiled C-terminus and a well defined helical N terminus7,8. C3d consists of an acidic residue lined electronegative depression that is away from the antigen binding site. This depression can bind the receptor which is electropositive in nature9.
Mode of action
C3a exerts its functions by binding to the G protein coupled receptor-C3a receptor. Upon binding of C3a to the receptor cAMP levels are triggered which in turn activates downstream signaling pathways10.
A receptor for C3d fragment of C3dg exists on B lymphocytes, B lymphoblastoid cell lines, and follicular dendriatic cells. This receptor, termed complement receptor (CR2), is important in B lymphocyte proliferation and differentiation. CR2 interacts with each of the C3 fragments containing residues 1209 to 1236 of C3d very strongly with C3d11,12.
Functions
C3a plays an important role in chemotaxis13. It increases the production of cytokines such as IL-6 thereby influencing the immune response14. It is also important for liver regeneration after tissue injury15.
C3d acts as an adjuvant by binding the antigen to the B cell through the CR2 receptor hence enhancing B cell humoral responses16.
References
1. Hugli TE (1986). Biochemistry and biology of anaphylatoxins. Complement, 3 (3), 111–27.
2. Buchner H (1889). Uber die bakterientodtende, Wirkunk des zellenfrien Blutserums. Zentralbl Bakteriol, 5, 1-11.
3. Muller-EHJ (1968). Chemistry and reaction mechanisms of complement. Adv Immunol., 8,1-80.
4. Matveevskaya NS, Alyoshkin VA and Rozina MN (1995). Isolation of the C3 complement component and its C3d subunit from IY-1 fraction of Cohn's fractionation of human plasma. J of chromatography B: Biosciences and applications, 664, 1, 261-66.
5. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J (2009). The role of the anaphylatoxins in health and disease. Molecular Immunology [EPub ahead of print]
6.Bergmann-Leitner ES, Leitner WW, Tsokos GC (2006). Complement 3d: from molecular adjuvant to target of immune escape mechanisms. Clin Immunol., 121(2), 177-85.
7.Maarten HL De Brunn and Georg HF (1985). Human complement component C3: cDNA coding sequence and derived primary structure (DNA sequence analysis/proteolytic cleavage site/signal peptide/precursor protein/family of plasma proteins. Proc. Natl. Acad. Sci. USA, 82, 708-712.
8.Nettesheim DG, Edalji RP, Mollison KW, Greer J, and Zuiderweg ER (1988). Secondary structure of complement component C3a anaphylatoxin in solution as determined by NMR spectroscopy: differences between crystal and solution conformations. Proc Natl Acad Sci USA, 85(14), 5036–5040.
9.Liliana C and David EI (2000). Structure-Guided Identification of C3d Residues Essential for Its Binding to Complement Receptor 2 (CD21)1. J Immunol., 165, 3839-3848.
10.Alison AH, Bao L, Christy AN, Craig L, Elliot I, Yuko F, Norma PG & Craig G (2000). A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406, 998-1001.
11.Köhl J (2006). Self, non-self, and danger: a complementary view. Adv Exp Med Biol., 586, 71-94.
12.Paul MK, Daniel SR, Si-Han H, Julie McM, William M and Anne S De G (2008). Novel function of complement C3d as an autologous helper T-cell target. Immunology and Cell Biology, 86, 221–225.
13.Britt S, Daniel B, Henry S, So¨ren G, Claudia R, Jo¨rg K, Wilfried B, and Andreas K (1999). Modulation of C3a Activity: Internalization of the Human C3a Receptor and its Inhibition by C5a1. J Immnunol., 162, 7409–7416.
14.Fischer WH, Jagels MA, Hugli TE (1999). Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3a(desArg). J Immunol.,1,162(1), 453-9.
15.Christopher WS, Maciej M, Dimitrios M, Ruxandra T, Lynn AS, Linda EG and John DL (2003). The Proinflammatory Mediators C3a and C5a Are Essential for Liver Regeneration. J Exp Med., 198, 6, 913-923.
16.Karen MH, Franklin RT, Julie AO, Jonathan CP, John HW, David RK, Joseph FB, Ted MR and Thomas FT (2004). Cutting Edge: C3d Functions as a Molecular Adjuvant in the Absence of CD21/35 Expression. J Immunol., 172 (10), 5833.
C3a is an anaphylotoxin and a cleavage product of the major complement protein C31. C3d, important for enhancing B cell responses is produced by cleavage of C3b which is also another product of C31.
Discovery
Complement system was first discovered in the 1880’s as a heat liable bactericidal activity componenet in fresh serum2. Later several components of the complement proteins were identified by protein purification techniques3. C3 and C3d were first isolated from the waste of industrially produced albumin in 19604.
Classification
C3a, C4a and C5a serum proteins of the complement system are all anaphylotoxins5. C3d belongs to the class of antigen binding proteins6.
Structural Characteristics
C3a is a 77 amino acid peptide with a random coiled C-terminus and a well defined helical N terminus7,8. C3d consists of an acidic residue lined electronegative depression that is away from the antigen binding site. This depression can bind the receptor which is electropositive in nature9.
Mode of action
C3a exerts its functions by binding to the G protein coupled receptor-C3a receptor. Upon binding of C3a to the receptor cAMP levels are triggered which in turn activates downstream signaling pathways10.
A receptor for C3d fragment of C3dg exists on B lymphocytes, B lymphoblastoid cell lines, and follicular dendriatic cells. This receptor, termed complement receptor (CR2), is important in B lymphocyte proliferation and differentiation. CR2 interacts with each of the C3 fragments containing residues 1209 to 1236 of C3d very strongly with C3d11,12.
Functions
C3a plays an important role in chemotaxis13. It increases the production of cytokines such as IL-6 thereby influencing the immune response14. It is also important for liver regeneration after tissue injury15.
C3d acts as an adjuvant by binding the antigen to the B cell through the CR2 receptor hence enhancing B cell humoral responses16.
References
1. Hugli TE (1986). Biochemistry and biology of anaphylatoxins. Complement, 3 (3), 111–27.
2. Buchner H (1889). Uber die bakterientodtende, Wirkunk des zellenfrien Blutserums. Zentralbl Bakteriol, 5, 1-11.
3. Muller-EHJ (1968). Chemistry and reaction mechanisms of complement. Adv Immunol., 8,1-80.
4. Matveevskaya NS, Alyoshkin VA and Rozina MN (1995). Isolation of the C3 complement component and its C3d subunit from IY-1 fraction of Cohn's fractionation of human plasma. J of chromatography B: Biosciences and applications, 664, 1, 261-66.
5. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J (2009). The role of the anaphylatoxins in health and disease. Molecular Immunology [EPub ahead of print]
6.Bergmann-Leitner ES, Leitner WW, Tsokos GC (2006). Complement 3d: from molecular adjuvant to target of immune escape mechanisms. Clin Immunol., 121(2), 177-85.
7.Maarten HL De Brunn and Georg HF (1985). Human complement component C3: cDNA coding sequence and derived primary structure (DNA sequence analysis/proteolytic cleavage site/signal peptide/precursor protein/family of plasma proteins. Proc. Natl. Acad. Sci. USA, 82, 708-712.
8.Nettesheim DG, Edalji RP, Mollison KW, Greer J, and Zuiderweg ER (1988). Secondary structure of complement component C3a anaphylatoxin in solution as determined by NMR spectroscopy: differences between crystal and solution conformations. Proc Natl Acad Sci USA, 85(14), 5036–5040.
9.Liliana C and David EI (2000). Structure-Guided Identification of C3d Residues Essential for Its Binding to Complement Receptor 2 (CD21)1. J Immunol., 165, 3839-3848.
10.Alison AH, Bao L, Christy AN, Craig L, Elliot I, Yuko F, Norma PG & Craig G (2000). A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406, 998-1001.
11.Köhl J (2006). Self, non-self, and danger: a complementary view. Adv Exp Med Biol., 586, 71-94.
12.Paul MK, Daniel SR, Si-Han H, Julie McM, William M and Anne S De G (2008). Novel function of complement C3d as an autologous helper T-cell target. Immunology and Cell Biology, 86, 221–225.
13.Britt S, Daniel B, Henry S, So¨ren G, Claudia R, Jo¨rg K, Wilfried B, and Andreas K (1999). Modulation of C3a Activity: Internalization of the Human C3a Receptor and its Inhibition by C5a1. J Immnunol., 162, 7409–7416.
14.Fischer WH, Jagels MA, Hugli TE (1999). Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3a(desArg). J Immunol.,1,162(1), 453-9.
15.Christopher WS, Maciej M, Dimitrios M, Ruxandra T, Lynn AS, Linda EG and John DL (2003). The Proinflammatory Mediators C3a and C5a Are Essential for Liver Regeneration. J Exp Med., 198, 6, 913-923.
16.Karen MH, Franklin RT, Julie AO, Jonathan CP, John HW, David RK, Joseph FB, Ted MR and Thomas FT (2004). Cutting Edge: C3d Functions as a Molecular Adjuvant in the Absence of CD21/35 Expression. J Immunol., 172 (10), 5833.
Calcitonins and Calcitonin Precursors Peptides
Definition
Calcitonin is a 32-amino acid linear polypeptide hormone produced primarily by the parafollicular cells in humans and ultimobranchial body in many other animals1. It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH). Calcitonin is a product of the CALC1 gene and is initially produced as a precursor1.
Discovery
Calcitonin was purified in 1962 by Copp and Cheney2. While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cells of the thyroid gland 3 .
Classification
CALC1 gene belongs to a superfamily of related protein hormone precursors that includes islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin 4 .
Structural Characteristics
Human calcitonin is a 32 amino acid peptide and is formed from procalcitonin (Cleavage products: Calcitonin, Katalin and a protein fragment)5. It has an N-terminal disulphide bridge and a C-terminal prolineamide residue, shown to potently inhibit bone resorption5. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP) 5.
Mode of action
Calcitonin exerts its functions by binding to calcitonin receptor that is a G-protein coupled receptor. Upon binding, the receptor triggers the formation of cAMP, a second messanger which in turn activates various signaling pathways in the target cell (Eg: Osteoblasts) 6 .
Functions
Calcitonin is mainly involved in the metabolism of Ca and phosphorous in the cell. Calcitonin secretion is stimulated by rise in Ca levels in the body. It inhibits Ca intake by the intestine and also prevent loss of Ca from the bones during pregnancy and lactation7It also inhibits osteoclast activity in the bones8. This property of calcitonin is utilized for treatment of osteoporosis and osteoarthritis and recently has been tried for bone metastasis1.Procalcitonin is released during severe infection where it is involved in Ca homeostasis. It is also used as a marker for sepsis8.
References:
1. Inzerillo AM, Zaidi M, Huang CL (2004). Calcitonin: physiological actions and clinical applications. J Pediatr Endocrinol Metab., 17(7), 931-40.
2. Copp DH, Cheney B (1962). Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood. Nature, 193, 381–2.
3. Stevenson JC, Evans IM (1981). Pharmacology and therapeutic use of calcitonin. Drugs, 21(4), 257-72.
4. Zaidi M, Inzerillo AM, Moonga BS, Bevis PJ, Huang CL (2002). Forty years of calcitonin--where are we now? A tribute to the work of Iain Macintyre, FRS, Bone, 30(5), 655-63.
5. Andreotti G, Méndez BL, Amodeo P, Morelli MA, Nakamuta H, Motta A (2006). "Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic alpha-helix". J. Biol. Chem., 281 (34), 24193–203.
6. Purdue BW, Tilakaratne N, Sexton PM (2002). Molecular pharmacology of the calcitonin receptor. Recept. Channels, 8 (3-4), 243–55.
7. Woodrow JP, Sharpe CJ, Fudge NJ, Hoff AO, Gagel RF, Kovacs CS (2006). Calcitonin plays a critical role in regulating skeletal mineral metabolism during lactation. Endocrinology, 147(9), 4010-21.
8. BalcI C, Sungurtekin H, Gürses E, Sungurtekin U, Kaptanoglu B (2003). Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit. Crit Care, 7 (1), 85–90
Calcitonin is a 32-amino acid linear polypeptide hormone produced primarily by the parafollicular cells in humans and ultimobranchial body in many other animals1. It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH). Calcitonin is a product of the CALC1 gene and is initially produced as a precursor1.
Discovery
Calcitonin was purified in 1962 by Copp and Cheney2. While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cells of the thyroid gland 3 .
Classification
CALC1 gene belongs to a superfamily of related protein hormone precursors that includes islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin 4 .
Structural Characteristics
Human calcitonin is a 32 amino acid peptide and is formed from procalcitonin (Cleavage products: Calcitonin, Katalin and a protein fragment)5. It has an N-terminal disulphide bridge and a C-terminal prolineamide residue, shown to potently inhibit bone resorption5. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP) 5.
Mode of action
Calcitonin exerts its functions by binding to calcitonin receptor that is a G-protein coupled receptor. Upon binding, the receptor triggers the formation of cAMP, a second messanger which in turn activates various signaling pathways in the target cell (Eg: Osteoblasts) 6 .
Functions
Calcitonin is mainly involved in the metabolism of Ca and phosphorous in the cell. Calcitonin secretion is stimulated by rise in Ca levels in the body. It inhibits Ca intake by the intestine and also prevent loss of Ca from the bones during pregnancy and lactation7It also inhibits osteoclast activity in the bones8. This property of calcitonin is utilized for treatment of osteoporosis and osteoarthritis and recently has been tried for bone metastasis1.Procalcitonin is released during severe infection where it is involved in Ca homeostasis. It is also used as a marker for sepsis8.
References:
1. Inzerillo AM, Zaidi M, Huang CL (2004). Calcitonin: physiological actions and clinical applications. J Pediatr Endocrinol Metab., 17(7), 931-40.
2. Copp DH, Cheney B (1962). Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood. Nature, 193, 381–2.
3. Stevenson JC, Evans IM (1981). Pharmacology and therapeutic use of calcitonin. Drugs, 21(4), 257-72.
4. Zaidi M, Inzerillo AM, Moonga BS, Bevis PJ, Huang CL (2002). Forty years of calcitonin--where are we now? A tribute to the work of Iain Macintyre, FRS, Bone, 30(5), 655-63.
5. Andreotti G, Méndez BL, Amodeo P, Morelli MA, Nakamuta H, Motta A (2006). "Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic alpha-helix". J. Biol. Chem., 281 (34), 24193–203.
6. Purdue BW, Tilakaratne N, Sexton PM (2002). Molecular pharmacology of the calcitonin receptor. Recept. Channels, 8 (3-4), 243–55.
7. Woodrow JP, Sharpe CJ, Fudge NJ, Hoff AO, Gagel RF, Kovacs CS (2006). Calcitonin plays a critical role in regulating skeletal mineral metabolism during lactation. Endocrinology, 147(9), 4010-21.
8. BalcI C, Sungurtekin H, Gürses E, Sungurtekin U, Kaptanoglu B (2003). Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit. Crit Care, 7 (1), 85–90
Calcitonin Gene-Related Peptides (CGRP) and Fragments
Definition
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide with potent receptor mediated vasodilatory and cardioexcitatory properties1.
Discovery
It was discovered when alternative processing of RNA transcripts from the calcitonin gene were shown to result in the production of distinct mRNAs encoding CGRP2. A human form of CGRP was isolated from thyroid tissue of patients with medullary thyroid carcinoma3.
Classification
CGRP belongs to the regulatory-peptide family that also includes adrenomedullin and amylin4.
Structural Characteristics
CGRP consists of an amino-terminal disulphide bridge linked loop between amino acids 2 and 7 followed by alpha helix between amino acids 8 and 18 and a poorly defined turn between residues 19 and 215. The carboxy and amino terminals of CGRP can interact independently with its receptors5.
Mode of action
CGRP exerts its function by binding to two G-protein coupled receptors, CGRP1 and CGRP2. One of the major functions of CGRP is vasodilation of cardiac muscles5. In order to achieve this, CGRP first binds to CGRP1 receptor which results in the production of cAMP which in turn activates Protein Kinase A (PKA)6. PKA phosphorylates and opens potassium channels that cause relaxation of muscles6.
Functions
CGRP is widely distributed in the central and peripheral nervous systems5. It produces vascular relaxation via binding to CGRP1 receptor5. Studies in mice have shown that CGRP may play a role in controlling blood pressure5. CGRP also protects tissue injury through its vasodilatory functions. Through its activity as a vasodilator, CGRP influence the activity of inflammatory cells by recruiting more cells at the site of inflammation7. CGRP plays a role in migraine as it is found that its levels raise during painful phases of the disease8. CGRP plays a protective role in cardiac tissue. The infusion of CGRP is beneficial in increasing cardiac output and lowering blood pressure in patients with congestive heart failure5.
References
1.Tortorella C, Macchi C, Forneris M and Nussdorfer GG (2001). Calcitonin gene-related peptide (CGRP), acting via CGRP type 1 receptors, inhibits potassium-stimulated aldosterone secretion and enhances basal catecholamine secretion from rat adrenal gland. Int. J Mol. Med., 8(3), 261-4.
2.Amara SG, Jonas V, Rosenfeld MG, Ong ES and Evans RM (1982). Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature, 298, 240–244.
3.Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergsma DJ, and Li Y (1996). A cDNA encoding the Calcitonin Generelated peptide type 1 receptor. J Biol Chem., 271, 11325–11329.
4.Bell D and McDermott BJ (1996). Calcitonin gene-related peptide in the cardiovascular system: characterization of receptor populations and their (patho)physiological significance. Pharmacol Rev., 48, 253–288.
5.Susan DB and Andrew DG (2004). Vascular Actions of Calcitonin Gene-Related Peptide and Adrenomedullin. Physiol Rev., 84, 903-934.
6.Hirata Y, Takagi Y, Takata S, Fukuda Y, Yoshimi H, and Fujita T (1988). Calcitonin gene-related peptide receptor in cultured vascular smooth muscle and endothelial cells. Biochem Biophys Res Commun., 151, 1113–1121.
7.Lambrecht BN (2001). Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation. Respir Res., 2, 133–138.
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide with potent receptor mediated vasodilatory and cardioexcitatory properties1.
Discovery
It was discovered when alternative processing of RNA transcripts from the calcitonin gene were shown to result in the production of distinct mRNAs encoding CGRP2. A human form of CGRP was isolated from thyroid tissue of patients with medullary thyroid carcinoma3.
Classification
CGRP belongs to the regulatory-peptide family that also includes adrenomedullin and amylin4.
Structural Characteristics
CGRP consists of an amino-terminal disulphide bridge linked loop between amino acids 2 and 7 followed by alpha helix between amino acids 8 and 18 and a poorly defined turn between residues 19 and 215. The carboxy and amino terminals of CGRP can interact independently with its receptors5.
Mode of action
CGRP exerts its function by binding to two G-protein coupled receptors, CGRP1 and CGRP2. One of the major functions of CGRP is vasodilation of cardiac muscles5. In order to achieve this, CGRP first binds to CGRP1 receptor which results in the production of cAMP which in turn activates Protein Kinase A (PKA)6. PKA phosphorylates and opens potassium channels that cause relaxation of muscles6.
Functions
CGRP is widely distributed in the central and peripheral nervous systems5. It produces vascular relaxation via binding to CGRP1 receptor5. Studies in mice have shown that CGRP may play a role in controlling blood pressure5. CGRP also protects tissue injury through its vasodilatory functions. Through its activity as a vasodilator, CGRP influence the activity of inflammatory cells by recruiting more cells at the site of inflammation7. CGRP plays a role in migraine as it is found that its levels raise during painful phases of the disease8. CGRP plays a protective role in cardiac tissue. The infusion of CGRP is beneficial in increasing cardiac output and lowering blood pressure in patients with congestive heart failure5.
References
1.Tortorella C, Macchi C, Forneris M and Nussdorfer GG (2001). Calcitonin gene-related peptide (CGRP), acting via CGRP type 1 receptors, inhibits potassium-stimulated aldosterone secretion and enhances basal catecholamine secretion from rat adrenal gland. Int. J Mol. Med., 8(3), 261-4.
2.Amara SG, Jonas V, Rosenfeld MG, Ong ES and Evans RM (1982). Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature, 298, 240–244.
3.Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergsma DJ, and Li Y (1996). A cDNA encoding the Calcitonin Generelated peptide type 1 receptor. J Biol Chem., 271, 11325–11329.
4.Bell D and McDermott BJ (1996). Calcitonin gene-related peptide in the cardiovascular system: characterization of receptor populations and their (patho)physiological significance. Pharmacol Rev., 48, 253–288.
5.Susan DB and Andrew DG (2004). Vascular Actions of Calcitonin Gene-Related Peptide and Adrenomedullin. Physiol Rev., 84, 903-934.
6.Hirata Y, Takagi Y, Takata S, Fukuda Y, Yoshimi H, and Fujita T (1988). Calcitonin gene-related peptide receptor in cultured vascular smooth muscle and endothelial cells. Biochem Biophys Res Commun., 151, 1113–1121.
7.Lambrecht BN (2001). Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation. Respir Res., 2, 133–138.
Vaccine Adjuvants: role and mechanisms of action in vaccine immunogenicity
Inactivated vaccines require adjuvants to stimulate an immune response. The choice of adjuvant or immune enhancer determines whether the immune response is effective, ineffective or damaging. Accordingly, there is a need for new adjuvants that stimulate the appropriate immunity, for example, T cell immunity for intracellular pathogens and cancer vaccines. In several adjuvants, the identification of chemical groups that interact with specific cell-toll like receptors (innate immunity) or receptors for co-stimulatory ligands (adaptive immunity), has enabled the establishment of structure-function relationships that are useful in the design of new adjuvants. Because of the crucial immunomodulating role of adjuvants, sub-unit vaccine development will remain dependant of new adjuvants.
Dynorphin, Analogs and Sequences
Definition
Dynorphins are a class of endogenous opioid peptides produced in many different parts of the brain, including the hypothalamus, the hippocampus and the spinal cord, and have many different physiological actions, depending upon the site of production.
Related peptides
Dynorphins arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, “big dynorphin” and a/ß-neo-endorphin1.
Discovery
Dynophin was discovered in the mid 1970's in the laboratory of Avram Goldstein, one of the most important researchers in the field of opioid receptors and endogenous opioid peptides. The molecular identification was achieved by Goldstein in collaboration with the Japanese biochemist, Shinro Tachibana for purification, and M. Hunkapiller and L. Hood, who performed the microsequencing.
Structural characteristics
A 4,000-dalton dynorphin (also called the “Big dynorphin”) was isolated from porcine pituitary. It has 32 amino acids, with a heptadecapeptide (17 amino acid sequence), called dynorphin A, at its amino terminus and a related tridecapeptide (13 amino acid sequence), dynorphin B, at its carboxyl terminus. The two peptides are separated by the "processing signal" Lys-Arg2.
Mechanism of action
Dynorphins primarily exert their effects through a G-protein coupled receptor called the ?-opioid receptor (KOR) 3. Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the µ-opioid receptor (MOR), d-opioid receptor (DOR), N-methyl-D-aspartic acid (NMDA)-type glutamate receptor, and bradykinin receptor. Different dynorphins show different receptor selectivities and potencies at receptors. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B. Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals, which leads to drug tolerance and withdrawal symptoms.
Functions
Dynorphins modulate pain response. They can significantly inhibit morphine- or beta-endorphin-induced analgesia4. Dynorphins inhibit dopamine release that would counter the pleasurable effects of cocaine5. They are important in maintaining homeostasis through appetite control and circadian rhythms6. In addition to their role in weight control, dynorphins have also been found to regulate body temperature7.
References
1.Day, R., Lazure, C., Basak, A., Boudreault, A., Limperis, P., Dong, W., et al. (1998). Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity. J Biol. Chem., 273(2), 829-836.
2.W Fischli, A Goldstein, M W Hunkapiller, and L E Hood (1982). Isolation and amino acid sequence analysis of a 4,000-dalton dynorphin from porcine pituitary. PNAS, 79 (17), 5435-5437.
3.Nyberg, F. & Hallburg, M. (2007). Neuropeptides in hyperthermia. Progress in brain research, 162:277-93.
4.FC Tulunay, MF Jen, JK Chang, HH Loh and NM Lee, (1981). Possible regulatory role of dynorphin on morphine- and beta-endorphin- induced analgesia. American Society for Pharmacology and Experimental Therapeutics, 219 (2), 296-298.
5.Clavin, W. (2005). Dynorphin: Nature’s Own Antidote to Cocaine (and Pleasure?).
6.Przewlocki, R., Lason, W., Konecka, A. M., Gramsch, C., Herz, A., & Reid, L. D. (1983). The opioid peptide dynorphin, circadian rhythms, and starvation. Science, 219(4580), 71-73.
7.Xin, L., Geller, E. B., & Adler, M. W. (1997). Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain.
Dynorphins are a class of endogenous opioid peptides produced in many different parts of the brain, including the hypothalamus, the hippocampus and the spinal cord, and have many different physiological actions, depending upon the site of production.
Related peptides
Dynorphins arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, “big dynorphin” and a/ß-neo-endorphin1.
Discovery
Dynophin was discovered in the mid 1970's in the laboratory of Avram Goldstein, one of the most important researchers in the field of opioid receptors and endogenous opioid peptides. The molecular identification was achieved by Goldstein in collaboration with the Japanese biochemist, Shinro Tachibana for purification, and M. Hunkapiller and L. Hood, who performed the microsequencing.
Structural characteristics
A 4,000-dalton dynorphin (also called the “Big dynorphin”) was isolated from porcine pituitary. It has 32 amino acids, with a heptadecapeptide (17 amino acid sequence), called dynorphin A, at its amino terminus and a related tridecapeptide (13 amino acid sequence), dynorphin B, at its carboxyl terminus. The two peptides are separated by the "processing signal" Lys-Arg2.
Mechanism of action
Dynorphins primarily exert their effects through a G-protein coupled receptor called the ?-opioid receptor (KOR) 3. Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the µ-opioid receptor (MOR), d-opioid receptor (DOR), N-methyl-D-aspartic acid (NMDA)-type glutamate receptor, and bradykinin receptor. Different dynorphins show different receptor selectivities and potencies at receptors. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B. Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals, which leads to drug tolerance and withdrawal symptoms.
Functions
Dynorphins modulate pain response. They can significantly inhibit morphine- or beta-endorphin-induced analgesia4. Dynorphins inhibit dopamine release that would counter the pleasurable effects of cocaine5. They are important in maintaining homeostasis through appetite control and circadian rhythms6. In addition to their role in weight control, dynorphins have also been found to regulate body temperature7.
References
1.Day, R., Lazure, C., Basak, A., Boudreault, A., Limperis, P., Dong, W., et al. (1998). Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity. J Biol. Chem., 273(2), 829-836.
2.W Fischli, A Goldstein, M W Hunkapiller, and L E Hood (1982). Isolation and amino acid sequence analysis of a 4,000-dalton dynorphin from porcine pituitary. PNAS, 79 (17), 5435-5437.
3.Nyberg, F. & Hallburg, M. (2007). Neuropeptides in hyperthermia. Progress in brain research, 162:277-93.
4.FC Tulunay, MF Jen, JK Chang, HH Loh and NM Lee, (1981). Possible regulatory role of dynorphin on morphine- and beta-endorphin- induced analgesia. American Society for Pharmacology and Experimental Therapeutics, 219 (2), 296-298.
5.Clavin, W. (2005). Dynorphin: Nature’s Own Antidote to Cocaine (and Pleasure?).
6.Przewlocki, R., Lason, W., Konecka, A. M., Gramsch, C., Herz, A., & Reid, L. D. (1983). The opioid peptide dynorphin, circadian rhythms, and starvation. Science, 219(4580), 71-73.
7.Xin, L., Geller, E. B., & Adler, M. W. (1997). Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain.
Band 3 Protein Fragments
Definition
Band 3 protein fragments are phylogenetically preserved transport peptides located on the organelle membranes especially the erythrocyte membrane where they mediate anion exchange1.
Discovery
Band 3 peptides were originally identified following SDS-gel electrophoresis of erythrocyte cell membrane. The large third band on the gel turned out to be the peptide. Hence the name Band 31.
Classification
Band 3 proteins are members of anion-exchange (AE) family of proteins2. AE proteins are encoded by a multigene family that has atleast three genes, AE1, AE2, AE3 and several splicioforms2. They are all expressed by most cells, e.g., erythrocytes, cardiomyocytes.
Structural Characteristics
Band 3 fragments have two functional domains.The integral domain mediates a 1:1 exchange of inorganic anions across the membrane, whereas the cytoplasmic domain provides binding sites for cytoskeletal proteins, glycolytic enzymes, and hemoglobin3. Activation of Band 3 fragments occurs through tyrosine phosphorylation4.
Mode of action
Band 3 peptide is bound to the erythrocyte membrane5. Its N-terminal region protrudes from the main body towards the red cell cytoplasm allowing it to interact with various membrane bound and cytoplasmic red cell components such as glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase and phosphofructokinase as well as other membrane components such as ankyrin and protein 4.15,6. Recently it has been found that Band 3 also binds to Hemoglobin. Interaction of Band 3 with these proteins exerts several changes in the cells for example lowering oxygen affinity of Hemoglobin5.
Functions
Band 3 fragments are involved in the anion-exchange across the plasma membrane on a one-for-one basis. This is crucial for CO2 uptake by the red cell and conversion into a proton and a bicarbonate ion that is then extruded from the cell by the band 3 molecule2. Band 3 serves as a physical linkage between the plasma membrane and the underlying membrane skeleton via binding with ankyrin and protein 4.15. This appears to prevent membrane surface loss. A spliced variant of Band 3 nAE1 regulates pH in cardioventricular myocytes through anion-exchange2. Band 3 is also an allosteric regulator of Heamoglobin as it binds to Hb and decreases its affinity for oxygen5. Other functions of Band 3 fragments include maintenance of cell volume and osmotic homeostasis, red cell aging, IgG binding and cellular removal7. Band 3 alterations are implicated in neurological diseases such as familial paroxysmal dyskinesia, idiopathic generalized epilepsies, and neuro- or choreoacanthocytosis7.
References
1.Hunter M (1977). Human erythrocyte anion permeabilities measured under conditions of net charge transfer. J Physiol, 268 (1): 35–49.
2.Richards SM, Jaconi ME, Vassort G and Puceat M (1999). A spliced variant of AE1 gene encodes a truncated form of Band 3 in heart: the predominant anion exchanger in ventricular myocytes.
3.Jonathan DG, Lin W and Michael JAT (1998). Complementation studies with co-expressed fragments of human red cell band 3 (AE1): the assembly of the anion-transport domain in Xenopus oocytes and a cell-free translation system. Biochem. J., 332, 161-171.
4.Yannoukakos D, Vasseur C, Piau JP, Wajcman H, Bursaux E (1991). Phosphorylation sites in human erythrocyte band 3 protein. Biochim. Biophys. Acta, 1061, 253-266.
5.Yuxun Z, Lois RM, Jill F, Orah P and James MM (2003), Human Erythrocyte Membrane Band 3 Protein Influences Hemoglobin Cooperativity: Possible effect on oxygen transport. J. Biol. Chem., 278, 41, 39565-39571.
6.Chambers EJ, Askin D, Bloomberg GB, et al. (1998). Studies on the structure of a transmembrane region and a cytoplasmic loop of the human red cell anion exchanger (band 3, AE1), Biochem. Soc. Trans., 26 (3): 516–20.
7.Kay MM (2004). Band 3 and its alterations in health and disease. Cell Mol Bio, 52, 117-38.
Band 3 protein fragments are phylogenetically preserved transport peptides located on the organelle membranes especially the erythrocyte membrane where they mediate anion exchange1.
Discovery
Band 3 peptides were originally identified following SDS-gel electrophoresis of erythrocyte cell membrane. The large third band on the gel turned out to be the peptide. Hence the name Band 31.
Classification
Band 3 proteins are members of anion-exchange (AE) family of proteins2. AE proteins are encoded by a multigene family that has atleast three genes, AE1, AE2, AE3 and several splicioforms2. They are all expressed by most cells, e.g., erythrocytes, cardiomyocytes.
Structural Characteristics
Band 3 fragments have two functional domains.The integral domain mediates a 1:1 exchange of inorganic anions across the membrane, whereas the cytoplasmic domain provides binding sites for cytoskeletal proteins, glycolytic enzymes, and hemoglobin3. Activation of Band 3 fragments occurs through tyrosine phosphorylation4.
Mode of action
Band 3 peptide is bound to the erythrocyte membrane5. Its N-terminal region protrudes from the main body towards the red cell cytoplasm allowing it to interact with various membrane bound and cytoplasmic red cell components such as glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase and phosphofructokinase as well as other membrane components such as ankyrin and protein 4.15,6. Recently it has been found that Band 3 also binds to Hemoglobin. Interaction of Band 3 with these proteins exerts several changes in the cells for example lowering oxygen affinity of Hemoglobin5.
Functions
Band 3 fragments are involved in the anion-exchange across the plasma membrane on a one-for-one basis. This is crucial for CO2 uptake by the red cell and conversion into a proton and a bicarbonate ion that is then extruded from the cell by the band 3 molecule2. Band 3 serves as a physical linkage between the plasma membrane and the underlying membrane skeleton via binding with ankyrin and protein 4.15. This appears to prevent membrane surface loss. A spliced variant of Band 3 nAE1 regulates pH in cardioventricular myocytes through anion-exchange2. Band 3 is also an allosteric regulator of Heamoglobin as it binds to Hb and decreases its affinity for oxygen5. Other functions of Band 3 fragments include maintenance of cell volume and osmotic homeostasis, red cell aging, IgG binding and cellular removal7. Band 3 alterations are implicated in neurological diseases such as familial paroxysmal dyskinesia, idiopathic generalized epilepsies, and neuro- or choreoacanthocytosis7.
References
1.Hunter M (1977). Human erythrocyte anion permeabilities measured under conditions of net charge transfer. J Physiol, 268 (1): 35–49.
2.Richards SM, Jaconi ME, Vassort G and Puceat M (1999). A spliced variant of AE1 gene encodes a truncated form of Band 3 in heart: the predominant anion exchanger in ventricular myocytes.
3.Jonathan DG, Lin W and Michael JAT (1998). Complementation studies with co-expressed fragments of human red cell band 3 (AE1): the assembly of the anion-transport domain in Xenopus oocytes and a cell-free translation system. Biochem. J., 332, 161-171.
4.Yannoukakos D, Vasseur C, Piau JP, Wajcman H, Bursaux E (1991). Phosphorylation sites in human erythrocyte band 3 protein. Biochim. Biophys. Acta, 1061, 253-266.
5.Yuxun Z, Lois RM, Jill F, Orah P and James MM (2003), Human Erythrocyte Membrane Band 3 Protein Influences Hemoglobin Cooperativity: Possible effect on oxygen transport. J. Biol. Chem., 278, 41, 39565-39571.
6.Chambers EJ, Askin D, Bloomberg GB, et al. (1998). Studies on the structure of a transmembrane region and a cytoplasmic loop of the human red cell anion exchanger (band 3, AE1), Biochem. Soc. Trans., 26 (3): 516–20.
7.Kay MM (2004). Band 3 and its alterations in health and disease. Cell Mol Bio, 52, 117-38.
Thursday, July 2, 2009
CDR-H3/C2
Definition
Complementarity-determining regions (CDRs) are hypervariable loop structures in the antigen-binding parts of antibodies and determine the specificity of antigen binding1. Improvement of antibody affinity may be obtained by site-directed mutagenesis of individual amino acid residues in the antibody CDRs1. CDR-H3/C2 is a peptide derived from the third heavy chain domain and modified by cyclization. It is capable of neutralizing HIV-1 replication1.
Discovery
CDR-H3/C2 was constructed in 1993 using sequences of mouse monoclonal antibody F58 that has the capacity to neutralize HIV-11.
Classification
CDR-H3/C2 belongs to the immunoglobulin superfamily of peptides1.
Structural Characteristics
CDR-H3/C2 is a 16 amino acid peptide with the sequence- CDLIYYDYEEDYYFDC, the ends of which are held by a disulphide bond to form a cyclic structure1.
Mode of action
CDR-H3/C2 binds effectively to HIV-1 variable region V3 and most likely preventing the interaction of HIV-1 to antibodies on the host cell1. This in turn inhibits infection of HIV into the host cell1.
Functions
CDR-H3/C2 is a neutralizing peptide for HIV-11.
References
1.Levi M, Sällberg M, Rudén U, Herlyn D, Maruyama H, Wigzell H, Marks J, Wahren B (1993). A complementarity-determining region synthetic peptide acts as a miniantibody and neutralizes human immunodeficiency virus type 1 in vitro. Proc Natl Acad Sci, 90(10), 4374-8.
Complementarity-determining regions (CDRs) are hypervariable loop structures in the antigen-binding parts of antibodies and determine the specificity of antigen binding1. Improvement of antibody affinity may be obtained by site-directed mutagenesis of individual amino acid residues in the antibody CDRs1. CDR-H3/C2 is a peptide derived from the third heavy chain domain and modified by cyclization. It is capable of neutralizing HIV-1 replication1.
Discovery
CDR-H3/C2 was constructed in 1993 using sequences of mouse monoclonal antibody F58 that has the capacity to neutralize HIV-11.
Classification
CDR-H3/C2 belongs to the immunoglobulin superfamily of peptides1.
Structural Characteristics
CDR-H3/C2 is a 16 amino acid peptide with the sequence- CDLIYYDYEEDYYFDC, the ends of which are held by a disulphide bond to form a cyclic structure1.
Mode of action
CDR-H3/C2 binds effectively to HIV-1 variable region V3 and most likely preventing the interaction of HIV-1 to antibodies on the host cell1. This in turn inhibits infection of HIV into the host cell1.
Functions
CDR-H3/C2 is a neutralizing peptide for HIV-11.
References
1.Levi M, Sällberg M, Rudén U, Herlyn D, Maruyama H, Wigzell H, Marks J, Wahren B (1993). A complementarity-determining region synthetic peptide acts as a miniantibody and neutralizes human immunodeficiency virus type 1 in vitro. Proc Natl Acad Sci, 90(10), 4374-8.
Delta-Sleep Inducing Peptide (DSIP) and Analogs
Definition
Delta sleep-inducing peptide (DSIP) is an endogenous neuropeptide that crosses the blood-brain barrier. It is associated with natural sleep and enhanced ectroencephalogram (EEG) delta rhythm.
Discovery
DSIP was isolated from the extracorporeal dislysate of cerebral venous blood in rabbits which was subjected to hypnogenic electrical stimulation1.
Classification.
The analogs of DSIP are synthesized by modification of the primary sequence of the nanopeptide. Phosphorylated DSIP, DSIP (1-4), DSIP (1-8), DSIP (2-8), DSIP (2-9), DSIP (5-9) etc are some of the analogs of DSIP.
Structural Characteristics
The primary amino acid sequence of DSIP is Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu with molecular weight of 848.8 kDa.
Mode of action
The action of DSIP is mediated by the activation of the serotoninergic system of the brain. It increases the activity of monoamine oxidase type A in mitochondria, the substrate of this enzyme is serotonin2.
Functions
DSIP has several physiological effects in addition to its ability to promote sleep in animals. It is also involved in neuroendocrine regulation and release of anterior pituitary hormones. In rodents and humans, DSIP influence in the secretion of adrenocorticotropic hormone (ACTH), luteinizing hormone (LH) and growth hormone (GH) 3,4,5,6. It also plays a role in the regulation of the circadian rhythms7.
References
1.Schoenenberger GA, Monnier M (1977). Characterization of a delta-electroencephalogram (-sleep)-inducing peptide. Proc Natl Acad Sci USA, 74, 1282-1286.
2.Shandra AA, Godlevskii LS, Brusentsov AI, Petrashevich VP, Vast'yanov RS, Nikel B, Mikhaleva II (1998). Delta-sleep-inducing peptide and its analogs and the serotoninergic system in the development of anticonvulsive influences. Neurosci Behav Physiol., 28(5), 521-526.
3.Sahu A, Klara SP (1987). Delta sleep inducing peptide (DSIP) stimulates LH releasein steroid-primed ovariectomized rats. Life Sci, 12, 1201-1206.
4.Okajima T, Hertting G (1986). Delta-sleep inducing peptide (DSIP) inhibited CRF-induced ACTH secretion from rat anterior pituitary gland in vitro. Horm Metab Res., 18, 497-499.
5.Iyer KS, McCann SM (1987) Delta sleep inducing peptide (DSIP) stimulates growthhormone (GH) release in the rat by hypothalamic and pituitary actions. Peptides, 8, 45-48
6.Chiodera P, Volpi R, Caapretti L, Giacalone G, Caffari G, Davoli C, Nigro E,Coiro V (1994) Different effects of delta-sleep-inducing peptide on arginine-vasopressin and ACTH secretion in normal men. Horm Res., 42, 267-272
7.S. Inoue, M. Kimura-Takeuchi, V. M. Koval'zon,V. N. Kalikhevich, and S. I. Churkina(1994). Effects of Some DSIP Peptide Analogs on Rat Sleep for Intraventricular Infusion. Bulletin of Experimental Biology and Medicine., 117, 58.
Delta sleep-inducing peptide (DSIP) is an endogenous neuropeptide that crosses the blood-brain barrier. It is associated with natural sleep and enhanced ectroencephalogram (EEG) delta rhythm.
Discovery
DSIP was isolated from the extracorporeal dislysate of cerebral venous blood in rabbits which was subjected to hypnogenic electrical stimulation1.
Classification.
The analogs of DSIP are synthesized by modification of the primary sequence of the nanopeptide. Phosphorylated DSIP, DSIP (1-4), DSIP (1-8), DSIP (2-8), DSIP (2-9), DSIP (5-9) etc are some of the analogs of DSIP.
Structural Characteristics
The primary amino acid sequence of DSIP is Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu with molecular weight of 848.8 kDa.
Mode of action
The action of DSIP is mediated by the activation of the serotoninergic system of the brain. It increases the activity of monoamine oxidase type A in mitochondria, the substrate of this enzyme is serotonin2.
Functions
DSIP has several physiological effects in addition to its ability to promote sleep in animals. It is also involved in neuroendocrine regulation and release of anterior pituitary hormones. In rodents and humans, DSIP influence in the secretion of adrenocorticotropic hormone (ACTH), luteinizing hormone (LH) and growth hormone (GH) 3,4,5,6. It also plays a role in the regulation of the circadian rhythms7.
References
1.Schoenenberger GA, Monnier M (1977). Characterization of a delta-electroencephalogram (-sleep)-inducing peptide. Proc Natl Acad Sci USA, 74, 1282-1286.
2.Shandra AA, Godlevskii LS, Brusentsov AI, Petrashevich VP, Vast'yanov RS, Nikel B, Mikhaleva II (1998). Delta-sleep-inducing peptide and its analogs and the serotoninergic system in the development of anticonvulsive influences. Neurosci Behav Physiol., 28(5), 521-526.
3.Sahu A, Klara SP (1987). Delta sleep inducing peptide (DSIP) stimulates LH releasein steroid-primed ovariectomized rats. Life Sci, 12, 1201-1206.
4.Okajima T, Hertting G (1986). Delta-sleep inducing peptide (DSIP) inhibited CRF-induced ACTH secretion from rat anterior pituitary gland in vitro. Horm Metab Res., 18, 497-499.
5.Iyer KS, McCann SM (1987) Delta sleep inducing peptide (DSIP) stimulates growthhormone (GH) release in the rat by hypothalamic and pituitary actions. Peptides, 8, 45-48
6.Chiodera P, Volpi R, Caapretti L, Giacalone G, Caffari G, Davoli C, Nigro E,Coiro V (1994) Different effects of delta-sleep-inducing peptide on arginine-vasopressin and ACTH secretion in normal men. Horm Res., 42, 267-272
7.S. Inoue, M. Kimura-Takeuchi, V. M. Koval'zon,V. N. Kalikhevich, and S. I. Churkina(1994). Effects of Some DSIP Peptide Analogs on Rat Sleep for Intraventricular Infusion. Bulletin of Experimental Biology and Medicine., 117, 58.
Subscribe to:
Posts (Atom)