Laminin Fragments

Definition
Laminins are the main constituents of basement membranes. These are heterotrimeric glycoproteins composed of a, ß and ? chains held together by disulfide bonds.

Discovery
Laminins were initially discovered by Timpl and Martin in 1979, from a murine fibrosarcoma 1. Laminins play important roles in cell adhesion, proliferation and differentiation and more than eleven LM chains and eleven LM isoforms have already been identified 2, 3. In the developing lung, mRNA for LM chains a1, ß1 and ?1 are detected in both epithelial and mesenchymal cells. LM-1 shares ß1 and ?1 chains with LM-2 and ß1 chain is also found in LM-6, LM- 8, and LM-10 3.

Structural Characteristics
Laminins are multidomain heterotrimers composed of a, ß and ? chains. Previously, laminin trimers were numbered with Arabic numerals in the order discovered, that is laminins-1 to -5. Aumailley et al., in 2005 introduced a new identification system for a trimer using three Arabic numerals, based on the alpha, beta and gamma chain numbers. The laminin with the chain composition a5ß? is termed laminin-511. Instead of the older Roman numeral nomenclature and mixed nomenclature, all modules are now called domains. Laminin epidermal growth factor-like (LE) domains are renumbered starting at the N-terminal, to be consistent with general protein nomenclature. Domain IVb of alpha chains is named laminin 4a (L4a), domain IVa of alpha chains is named L4b, domain IV of gamma chains is named L4, and domain IV of beta chains is named laminin four (LF). The two coiled-coil domains I and II are now considered one laminin coiled-coil domain (LCC). The interruption in the coiled-coil of beta chains is named laminin beta-knob (Lbeta) domain. The chain origin of a domain is specified by the chain nomenclature, such as alpha1L4a 4. Fourteen other chain combinations have been identified in vivo. The trimeric proteins form a cross, giving a structure that can bind to other cell membrane and extracellular matrix molecules 5. The three shorter arms are particularly good at binding to other laminin molecules, which allow them to form sheets. The long arm is capable of binding to cells, which helps anchor organized tissue cells to the membrane.

Mode of Action
Laminin is one of the main glycoproteins of the basement membrane and participates in a series of such biological phenomena such as adhesion, migration, cellular differentiation and the maintenance of the cytoskeleton upon its binding to several components of the matrix, such as collagen type IV, heparin sulphate and entacin 6 7. Laminin is thought to be synthesized by hepatocytes and sinusoidal cells. Stellate cells or lipocytes, produce the largest amount of serum laminin. With the development of hepatic cirrhosis, laminin and collagen deposition occurs both along the fibers of septal fibrosis and subendothelial sinusoids or Disse's space. At the latter site, laminin deposition, together with collagen deposition, determine the formation of a true basement membrane along sinusoids. This phenomenon is called capillarization of Disse's space 8. In the presence of Ca2+, some laminins self.assemble into a polymer through the interaction of their three NH2 termini. When lung organotypic cultures are exposed to a proteolytic fragment of laminin-1 that blocks laminin polymerization. This fragment, referred as E4, comprises the outer globular region of laminin chain. Inhibition of laminin polymerization in lung organotypic cultures resulted in impaired basement membrane assembly and failure of epithelial cells to polarize.

Functions
Networks function, laminins bind to cell membranes through integrin receptors and other plasma membrane molecules, such as the dystroglycan glycoprotein complex and Lutheran blood group glycoprotein. These interactions contribute to cell attachment and differentiation, cell shape and movement, maintenance of tissue phenotype, and promotion of tissue survival

Pathology, dysfunctional structure of one particular laminin, laminin-211, is the cause of one form of congenital muscular dystrophy. Malfunctional laminin-521 in the kidney filter causes leakage of protein into the urine and nephrotic syndrome 9.

In cell structure, recent studies have demonstrated that laminins can be used to culture cells, such as pluripotent stem cells, that are difficult to culture on other substrates. Laminin-111 as well as a mixture of laminins 511 and 521 from human placenta have been used10.

In neural development, Laminin-111 is a major substrate along which nerve axons will grow, both in vivo and in vitro. The presence of laminin-1 can influence the growth cone. For example, growth cones are repelled by netrin when grown on laminin-111, but are attracted to netrin when grown on fibronectin.

References
1. Timpl R, Rohde H, Robey PG, Rennard SI, Foidart JM, Martin GR (1979). Laminin – a glycoprotein from basement membranes. J Biol Chem., 254(19):9933-9937.
2. Engel. J (1993). Structure and function of laminin. In Molecular and cellular aspects of basement membranes. Academic Press., 43:147-176.
3. Timpi, R. (1996). Macromolecular organization of basement membrane. Opin.Cell Bioi., 8:618-624.
4. Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, Engel J, Engvall E, Hohenester E, Jones JC, Kleinman HK, Marinkovich MP, Martin GR, Mayer U, Meneguzzi G, Miner JH, Miyazaki K, Patarroyo M, Paulsson M, Quaranta V, Sanes JR, Sasaki T, Sekiguchi K, Sorokin LM, Talts JF, Tryggvason K, Uitto J, Virtanen I, von der Mark K, Wewer UM, Yamada Y, Yurchenco PD (2005). A simplified laminin nomenclature. Matrix Biol., 24 (5):326-332.
5. Haralson MA, John RH (1995). Extracellular matrix: a practical approach. Ithaca, N.Y: IRL Press.
6. Burgeson RE, Chiquet M, Deutzmann R, Ekblom P, Engel J, Kleinman H (1994). A new nomenclature for the laminins. Matrix Biol., 14:209-211.
7. Aumailley M, Smyth N (1998). The role of laminins in basement membrane function. J Anat., 193:1-21.
8. Schaffner F, Poper H (1963). Capillarization of hepatic sinusoids in man. Gastroenterology, 44:239-242.
9. Yurchenko P and Batton BL (2009). Developmental and pathogenic mechanisms of basement membrane assembly. Curr Pharm Des., 15(12):1277-1294.
10. Domogatskaya A, Rodin S, Boutaud A, Tryggvason K (2008). Laminin-511 but not -332, -111, or -411 enables mouse embryonic stem cell self-renewal in vitro. Stem Cells, 26(11):2800-2809.