A Novel Talin-to-RhoA Switch Mechanism Upon Ligand Binding of the Collagen VI Receptor CMG2

Abstract

The physiological role of Capillary Morphogenesis Gene 2 (CMG2), a receptor for both collagen VI and anthrax toxin, is poorly understood. Biallelic loss-of-function mutations produces the severe condition, Hyaline Fibromatosis Syndrome (HFS). We here report a novel mechanistic role for an extracellular matrix receptor. In contrast to integrins, CMG2 binds talin, and thereby the actin cytoskeleton, only in its ligand-free state. Upon extracellular ligand binding, CMG2 releases talin and accepts the binding of RhoA, an actin cytoskeleton regulator, and its effectors. We establish that HFS-associated mutations in the CMG2 cytosolic tail prevent talin binding, resulting in constitutive RhoA binding. Based on molecular dynamics simulations, we identify CMG2 residues responsible for talin or RhoA binding and demonstrated that effective switching between talin and RhoA binding is required for the intracellular degradation of collagen VI in mammalian cells as well as for the control of oriented cell division in fish development.