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Structure of the human myostatin precursor and determinants of growth factor latency.

Authors
  • Cotton, Thomas R1
  • Fischer, Gerhard1
  • Wang, Xuelu1
  • McCoy, Jason C2
  • Czepnik, Magdalena2
  • Thompson, Thomas B2
  • Hyvönen, Marko3
  • 1 Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • 2 Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, USA.
  • 3 Department of Biochemistry, University of Cambridge, Cambridge, UK [email protected]
Type
Published Article
Journal
The EMBO Journal
Publisher
EMBO
Publication Date
Feb 01, 2018
Volume
37
Issue
3
Pages
367–383
Identifiers
DOI: 10.15252/embj.201797883
PMID: 29330193
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Myostatin, a key regulator of muscle mass in vertebrates, is biosynthesised as a latent precursor in muscle and is activated by sequential proteolysis of the pro-domain. To investigate the molecular mechanism by which pro-myostatin remains latent, we have determined the structure of unprocessed pro-myostatin and analysed the properties of the protein in its different forms. Crystal structures and SAXS analyses show that pro-myostatin adopts an open, V-shaped structure with a domain-swapped arrangement. The pro-mature complex, after cleavage of the furin site, has significantly reduced activity compared with the mature growth factor and persists as a stable complex that is resistant to the natural antagonist follistatin. The latency appears to be conferred by a number of distinct features that collectively stabilise the interaction of the pro-domains with the mature growth factor, enabling a regulated stepwise activation process, distinct from the prototypical pro-TGF-β1. These results provide a basis for understanding the effect of missense mutations in pro-myostatin and pave the way for the design of novel myostatin inhibitors. © 2018 The Authors.

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