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.