Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations.
VWA domain
collagen
collagen VI
crystallography
electron microscopy (EM)
extracellular matrix
extracellular matrix protein
muscular dystrophy
myopathy
single-particle EM
single-particle analysis
small-angle X-ray scattering (SAXS)
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
04 09 2020
04 09 2020
Historique:
received:
22
06
2020
revised:
16
07
2020
pubmed:
29
7
2020
medline:
28
1
2021
entrez:
29
7
2020
Statut:
ppublish
Résumé
Collagen VI is a ubiquitous heterotrimeric protein of the extracellular matrix (ECM) that plays an essential role in the proper maintenance of skeletal muscle. Mutations in collagen VI lead to a spectrum of congenital myopathies, from the mild Bethlem myopathy to the severe Ullrich congenital muscular dystrophy. Collagen VI contains only a short triple helix and consists primarily of von Willebrand factor type A (VWA) domains, protein-protein interaction modules found in a range of ECM proteins. Disease-causing mutations occur commonly in the VWA domains, and the second VWA domain of the α3 chain, the N2 domain, harbors several such mutations. Here, we investigate structure-function relationships of the N2 mutations to shed light on their possible myopathy mechanisms. We determined the X-ray crystal structure of N2, combined with monitoring secretion efficiency in cell culture of selected N2 single-domain mutants, finding that mutations located within the central core of the domain severely affect secretion efficiency. In longer α3 chain constructs, spanning N6-N3, small-angle X-ray scattering demonstrates that the tandem VWA array has a modular architecture and samples multiple conformations in solution. Single-particle EM confirmed the presence of multiple conformations. Structural adaptability appears intrinsic to the VWA domain region of collagen VI α3 and has implications for binding interactions and modulating stiffness within the ECM.
Identifiants
pubmed: 32719005
pii: S0021-9258(17)49989-3
doi: 10.1074/jbc.RA120.014865
pmc: PMC7476709
doi:
Substances chimiques
COL6A3 protein, human
0
Collagen Type VI
0
Banques de données
PDB
['4IGI', '4CN8', '6SNK']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12755-12771Subventions
Organisme : Medical Research Council
ID : MR/K018779/1
Pays : United Kingdom
Informations de copyright
© 2020 Solomon-Degefa et al.
Déclaration de conflit d'intérêts
Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.
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