Von Willebrand factor A (VWA) domains are versatile protein interaction domains
with N and C termini in close proximity placing spatial constraints on overall
protein structure. The 1.2 Å crystal structures of a collagen VI VWA domain
and a disease-causing point mutant show C-terminal extensions that place the N
and C termini at opposite ends. This allows a "beads-on-a-string"
arrangement of multiple VWA domains as observed for ten N-terminal domains of
the collagen VI α3 chain. The extension is linked to the core domain by a salt
bridge and two hydrophobic patches. Comparison of the wild-type and a muscular
dystrophy-associated mutant structure identifies a potential perturbation of a
protein interaction interface and indeed, the secretion of mutant collagen VI
tetramers is affected. Homology modeling is used to locate a number of
disease-associated mutations and analyze their structural impact, which will
allow mechanistic analysis of collagen-VI-associated muscular dystrophy
phenotypes.
