Journal
EMBO JOURNAL
Volume 37, Issue 3, Pages 367-383Publisher
WILEY
DOI: 10.15252/embj.201797883
Keywords
GDF8; latency; myostatin; pro-domain; TGF-beta superfamily
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Funding
- Herchel Smith Scholarship
- National Institutes of Health [R01GM114640]
- Muscular Dystrophy Association Grant [240087]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM114640] Funding Source: NIH RePORTER
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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-b1. 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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