Structural highlights
Disease[GDF8_HUMAN] Myostatin-related muscle hypertrophy. The disease is caused by mutations affecting the gene represented in this entry. Function[GDF8_HUMAN] Acts specifically as a negative regulator of skeletal muscle growth. Publication Abstract from PubMedMyostatin, 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-beta1. 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. Structure of the human myostatin precursor and determinants of growth factor latency.,Cotton TR, Fischer G, Wang X, McCoy JC, Czepnik M, Thompson TB, Hyvonen M EMBO J. 2018 Jan 12. pii: embj.201797883. doi: 10.15252/embj.201797883. PMID:29330193[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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