6snk
From Proteopedia
Crystal structure of the Collagen VI alpha3 N2 domain
Structural highlights
DiseaseCO6A3_HUMAN Defects in COL6A3 are a cause of Bethlem myopathy (BM) [MIM:158810. BM is a rare autosomal dominant proximal myopathy characterized by early childhood onset (complete penetrance by the age of 5) and joint contractures most frequently affecting the elbows and ankles.[1] [2] [3] [4] [5] Defects in COL6A3 are a cause of Ullrich congenital muscular dystrophy (UCMD) [MIM:254090; also known as Ullrich scleroatonic muscular dystrophy. UCMD is an autosomal recessive congenital myopathy characterized by muscle weakness and multiple joint contractures, generally noted at birth or early infancy. The clinical course is more severe than in Bethlem myopathy.[6] [7] FunctionCO6A3_HUMAN Collagen VI acts as a cell-binding protein. Publication Abstract from PubMedCollagen 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 alpha3 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 alpha3 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 alpha3 and has implications for binding interactions and modulating stiffness within the ECM. Structure of a collagen VI alpha3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations.,Solomon-Degefa H, Gebauer JM, Jeffries CM, Freiburg CD, Meckelburg P, Bird LE, Baumann U, Svergun DI, Owens RJ, Werner JM, Behrmann E, Paulsson M, Wagener R J Biol Chem. 2020 Jul 21. pii: RA120.014865. doi: 10.1074/jbc.RA120.014865. PMID:32719005[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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