title: A structure of a collagen VI VWA domain displays N and C termini at opposite sides of the protein.
abstract: 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.
authors: Center for Biochemistry, Medical Faculty, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.
authors: Ann-Kathrin A
authors: AK
authors: Becker
authors: Centre for Biological Sciences, B85 Life Sciences Building M55, University of Southampton, Southampton SO17 1BJ, UK.
authors: Halina
authors: H
authors: Mikolajek
authors: Center for Biochemistry, Medical Faculty, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.
authors: Mats
authors: M
authors: Paulsson
authors: Center for Biochemistry, Medical Faculty, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany. Electronic address: raimund.wagener@uni-koeln.de.
authors: Raimund
authors: R
authors: Wagener
authors: Centre for Biological Sciences, B85 Life Sciences Building M55, University of Southampton, Southampton SO17 1BJ, UK. Electronic address: j.m.werner@soton.ac.uk.
authors: Jörn M
authors: JM
authors: Werner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D024142:Collagen Type VI / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014841:von Willebrand Factor / Q000737:chemistry
chemical_list: C553839:Col6a1 protein, human; C540085:Col6a1 protein, mouse; D024142:Collagen Type VI; D014841:von Willebrand Factor