Polymerizing laminins: Assembly, functions and disorders.

Laminins initiate basement membrane (BM) assembly by adhering to cells, establishing cytoskeletal links through integrin and dystroglycan receptors, and by polymerizing to form a sheet-like provisional matrix that recruits other BM components to complete assembly. Laminin polymerization is mediated by the LN domain tips of the three short arms that bind together to form "polymer nodes" connecting adjacent laminins. The first step of this assembly is the low affinity binding of a β-LN domain to a γ-LN domain, followed by a higher affinity binding of an α-LN domain to the β-γ complex. Negative staining, mutagenesis, and cryo-electron microscopic studies have revealed the polymer node is organized as a triskelion connected by "toe-to heel" LN interactions. A related structure using toe-to-heel LN interactions is seen in the polymer inhibiting complex formed when netrin-4 binds to laminin γ1. LAMA2-deficient related dystrophy, affecting muscle, peripheral nerve and brain, results from nonsense, missense, and deletion mutations of the LAMA2 gene. A clinical subset is caused by in-frame mutations in the α2-LN domain that prevent polymerization. A dystrophic mouse model (dy2J/dy2J) was used to develop a method of disease amelioration by expressing laminin-binding proteins that bear a functional α1-LN domain to enable polymerization. A model for the more common severe dystrophy (dy3K/dy3K), in which α2-laminins are replaced by α4-laminins, benefits from double expression of laminin-binding proteins that enable polymerization and that bind to dystroglycan. Such approaches, using adeno-associated virus (AAV) delivery of genes encoding these proteins, hold promise in the development of treatments for the human condition.