Abstract
Laminins are large cell-adhesive glycoproteins that are required for the formation and function of basement membranes in all animals. Structural studies by electron microscopy in the early 1980s revealed a cross-shaped molecule, which subsequently was shown to consist of three distinct polypeptide chains. Crystallographic studies since the mid-1990s have added atomic detail to all parts of the laminin heterotrimer. The three short arms of the cross are made up of continuous arrays of disulphide-rich domains. The globular domains at the tips of the short arms mediate laminin polymerization; the surface regions involved in this process have been identified by structure-based mutagenesis. The long arm of the cross is an α-helical coiled coil of all three chains, terminating in a cell-adhesive globular region. The molecular basis of cell adhesion to laminins has been revealed by recent structures of heterotrimeric integrin-binding fragments and of a laminin fragment bound to the carbohydrate modification of dystroglycan. The structural characterization of the laminin molecule is essentially complete, but we still have to find ways of imaging native laminin polymers at molecular resolution.
Highlights
two laboratories independently purified a large glycoprotein from the extracellular matrix produced by mouse tumour cells
Antibodies raised against this glycoprotein reacted with basement membranes
We now know that mammals have
Summary
About 40 years ago, two laboratories independently purified a large glycoprotein from the extracellular matrix produced by mouse tumour cells [1,2]. The recent crystal structures of E8-like fragments [35,36] showed that the coiled coil is attached perpendicularly to a triangular arrangement of domains LG1-3 of the α chain, with the γ1 tail nestled between LG1 and LG2 on the more accessible ’bottom’ surface of the LG1-3 triangle (Figure 4). An electron micrograph of integrin α6β1 bound to the laminin-511 E8 fragment shows the integrin approaching the LG domains from the opposite direction as the coiled coil [36], but a high-resolution structure is needed to understand how specificity is achieved Such a structure would provide invaluable information on the conformational regulation of laminin-binding integrins, which appears to deviate from the prevailing model derived from integrins containing the β2 and β3 subunits [51]. The LG1-3 and LG4-5 portions of laminin α chains are separated by a flexible linker, suggesting that integrin and matriglycan binding may not be mutually exclusive
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