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Structure of the human myostatin precursor and determinants of growth factor latency
Author(s) -
Cotton Thomas R,
Fischer Gerhard,
Wang Xuelu,
McCoy Jason C,
Czepnik Magdalena,
Thompson Thomas B,
Hyvönen Marko
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201797883
Subject(s) - myostatin , biology , follistatin , furin , growth differentiation factor , microbiology and biotechnology , transforming growth factor , growth factor , regulator , protein structure , proteolysis , biochemistry , receptor , gene , bone morphogenetic protein , enzyme
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.