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EMBO J. 2018 Feb 1;37(3):367-383. doi: 10.15252/embj.201797883. Epub 2018 Jan 12.

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

Author information

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 mh256@cam.ac.uk.

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.

KEYWORDS:

GDF8; TGF‐β superfamily; latency; myostatin; pro‐domain

PMID:
29330193
PMCID:
PMC5793801
DOI:
10.15252/embj.201797883
[Indexed for MEDLINE]

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