bioRxiv Biochemistry
bioRxiv Biochemistry
5 years ago

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

Cotton, Czepnik, J. C., M., Hyvonen, Thompson, Fischer, T. B., McCoy, Wang, G., T. R., X.
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 solved 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 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 step-wise activation process, distinct from the prototypical pro-TGF-{beta}1. 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.

Publisher URL: http://biorxiv.org/cgi/content/short/153403v1

DOI: 10.1101/153403

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