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

Authors
  • Cotton, Thomas R1
  • Fischer, Gerhard1, 2
  • Wang, Xuelu1
  • McCoy, Jason C3
  • Czepnik, Magdalena3
  • Thompson, Thomas B3
  • Hyvönen, Marko1
  • 1 University of Cambridge, UK , (United Kingdom)
  • 2 Boehringer Ingelheim RCV, Austria , (Austria)
  • 3 University of Cincinnati, USA , (United States)
Type
Published Article
Journal
The EMBO Journal
Publisher
EMBO
Publication Date
Jan 12, 2018
Volume
37
Issue
3
Pages
367–383
Identifiers
DOI: 10.15252/embj.201797883
PMID: 29330193
PMCID: PMC5793801
Source
PubMed Central
Keywords
License
Unknown
External links

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.

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