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Review
. 2013 Jan-Feb;7(1):56-63.
doi: 10.4161/cam.21831. Epub 2012 Oct 17.

Laminins in basement membrane assembly

Erhard Hohenester  1 , Peter D Yurchenco
Affiliations
Review

Laminins in basement membrane assembly

Erhard Hohenester et al. Cell Adh Migr. 2013 Jan-Feb.

Abstract

The heterotrimeric laminins are a defining component of all basement membranes and self-assemble into a cell-associated network. The three short arms of the cross-shaped laminin molecule form the network nodes, with a strict requirement for one α, one β and one γ arm. The globular domain at the end of the long arm binds to cellular receptors, including integrins, α-dystroglycan, heparan sulfates and sulfated glycolipids. Collateral anchorage of the laminin network is provided by the proteoglycans perlecan and agrin. A second network is then formed by type IV collagen, which interacts with the laminin network through the heparan sulfate chains of perlecan and agrin and additional linkage by nidogen. This maturation of basement membranes becomes essential at later stages of embryo development.

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Figures

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Figure 1. Domain structure and self-assembly of laminin-111. (A) Schematic drawing of the laminin-111 heterotrimer. The three short arms of the cross-shaped molecule have a common domain structure and consist of laminin N-terminal (LN) domains, laminin-type epidermal growth factor-like (LE) domains, and L4 domains, as indicated for the α1 chain. The α1 chain uniquely contains five laminin G-like (LG) domains. LG1-3 likely interact with the C-terminal residues of the γ1 chain. (B) The three-arm interaction model of laminin self-assembly. The ternary nodes in the network are formed by the N-terminal regions of one α, one β and one γ chain. The long arm of the laminin heterotrimer is not involved in network formation.
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Figure 2. Crystal structures of laminin fragments. Polypeptide chains are shown in cartoon representation, disulfide bonds as yellow sticks and calcium ions as magenta spheres. The N- and C-termini are labeled. (A) Crystal structure of the laminin α5 LN-LEa1-2 fragment. Three residues whose mutation abolishes the inhibitory activity of α5 LN-LEa1-2 on laminin-111 polymerization are shown as pink sticks. The dotted line indicates a loop region that is disordered in the α5 LN-LEa1-2 crystal structure; its general location can be inferred from structures of the related netrin G proteins., (B) Putative structure of the laminin LG1-5 region, assembled from crystal structures of the α2 LG1-3 and α1 LG4-5 fragments., The dotted lines indicate linker regions that were not resolved by the crystal structures. In the intact laminin heterotrimer, the LG1 domain is predicted to interact tightly with the LG2-3 pair (see text). Basic residues in LG4 whose mutation reduces α-DG, heparin and sulfatide binding are shown as pink sticks. The calcium ion in LG4 is essential for α-DG binding. (C) Crystal structure of the laminin γ1 LEb2-4 fragment (blue) bound to domain G3 of nidogen-1 (magenta). Two residues whose mutation abolishes nidogen-1 binding are shown as pink sticks.
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Figure 3. Schematic drawing of the molecular structure of a basement membrane. The laminin network is anchored to the cell surface by interactions of the long arms with cellular receptors (integrins, α-dystroglycan and sulfated glycolipids/sulfatides). Collateral interactions are made with the heparan sulfate proteoglycans agrin and perlecan. An independent network is formed by type IV collagen, through interactions of its N-terminal 7S and C-terminal NC1 domains, as well as through lateral associations of the triple helices. The laminin and collagen networks are linked by nidogen and heparan sulfates (black double-headed arrows).
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