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Solomon-Degefa H, Gebauer JM, Jeffries CM, et al. Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations. J Biol Chem. 2020;295(36):12755-12771doi: 10.1074/jbc.RA120.014865.
Solomon-Degefa, H., Gebauer, J. M., Jeffries, C. M., Freiburg, C. D., Meckelburg, P., Bird, L. E., Baumann, U., Svergun, D. I., Owens, R. J., Werner, J. M., Behrmann, E., Paulsson, M., & Wagener, R. (2020). Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations. The Journal of biological chemistry, 295(36), 12755-12771. https://doi.org/10.1074/jbc.RA120.014865
Solomon-Degefa, Herimela, et al. "Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations." The Journal of biological chemistry vol. 295,36 (2020): 12755-12771. doi: https://doi.org/10.1074/jbc.RA120.014865
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. Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations. J Biol Chem. 2020 Sep 04;295(36):12755-12771. doi: 10.1074/jbc.RA120.014865. Epub 2020 Jul 21. PMID: 32719005; PMCID: PMC7476709.
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J Biol Chem. 2020 Sep 04;295(36):12755-12771. doi: 10.1074/jbc.RA120.014865. Epub 2020 Jul 21.

Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations.

The Journal of biological chemistry

Herimela Solomon-Degefa, Jan M Gebauer, Cy M Jeffries, Carolin D Freiburg, Patrick Meckelburg, Louise E Bird, Ulrich Baumann, Dmitri I Svergun, Raymond J Owens, Jörn M Werner, Elmar Behrmann, Mats Paulsson, Raimund Wagener

Affiliations

  1. Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany.
  2. Institute of Biochemistry, University of Cologne, Cologne, Germany.
  3. European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany.
  4. The Research Complex at Harwell, Rutherford Appleton Laboratory Harwell, Oxford, United Kingdom.
  5. Structural Biology Division, Wellcome Human Genetics Centre, University of Oxford, Oxford, United Kingdom.
  6. School of Biological Sciences, University of Southampton, Southampton, United Kingdom.
  7. Max Planck Research Group Structural Dynamics of Proteins, Center of Advanced European Studies and Research (caesar), Bonn, Germany.
  8. Center for Molecular Medicine (CMMC), Cologne, Germany.
  9. Cologne Center for Musculoskeletal Biomechanics (CCMB), Cologne, Germany.
  10. Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany [email protected].

PMID: 32719005 PMCID: PMC7476709 DOI: 10.1074/jbc.RA120.014865

Abstract

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.

© 2020 Solomon-Degefa et al.

Keywords: 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)

Conflict of interest statement

Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.

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