Laminin Polymerization and Inherited Disease: Lessons From Genetics.

Liam Shaw,Kevin J Hamill,Conor J Sugden

doi:10.3389/fgene.2021.707087

Abstract

The laminins (LM) are a family of basement membranes glycoproteins with essential structural roles in supporting epithelia, endothelia, nerves and muscle adhesion, and signaling roles in regulating cell migration, proliferation, stem cell maintenance and differentiation. Laminins are obligate heterotrimers comprised of α, β and γ chains that assemble intracellularly. However, extracellularly these heterotrimers then assemble into higher-order networks via interaction between their laminin N-terminal (LN) domains. In vitro protein studies have identified assembly kinetics and the structural motifs involved in binding of adjacent LN domains. The physiological importance of these interactions has been identified through the study of pathogenic point mutations in LN domains that lead to syndromic disorders presenting with phenotypes dependent on which laminin gene is mutated. Genotype-phenotype comparison between knockout and LN domain missense mutations of the same laminin allows inferences to be drawn about the roles of laminin network assembly in terms of tissue function. In this review, we will discuss these comparisons in terms of laminin disorders, and the therapeutic options that understanding these processes have allowed. We will also discuss recent findings of non-laminin mediators of laminin network assembly and their implications in terms of basement membrane structure and function.

Highlights

Basement membranes (BMs) are flexible 40–120 nm sheets that separates cells from underlying connective tissue and regulate important cell behaviors such as cell polarity and migration, metabolism, and in inducing differentiation (Paulsson, 1992)
Most BMs consist of two layers; an electron-lucent layer, lamina lucida comprised predominantly of laminins (LMs) and nidogens, and an electron dense layer, lamina densa of type IV collagen and perlecan (Paulsson, 1992)
As LM411 is upregulated in MDC1A but cannot compensate for LM211 dysfunction, the nidogen/laminin N-terminal (LN) domain chimeric protein can be used to bind the γ1 chain of LM411 via the nidogen region and provide the missing αLN domain needed to allow LM411 polymerization (Reinhard et al, 2017)

Summary

Introduction

Basement membranes (BMs) are flexible 40–120 nm sheets that separates cells from underlying connective tissue and regulate important cell behaviors such as cell polarity and migration, metabolism, and in inducing differentiation (Paulsson, 1992). Patch 2 is not glycosylated nor conserved with β- or γ-chains but is important for polymerization as mutation of PLENGE residues in the β5-β6 loop all result in inhibition of polymerization (Hussain et al, 2011; Carafoli et al, 2012).

Results

Conclusion