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

      , , , , , ,

      The EMBO Journal

      EMBO

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          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.

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          Author and article information

          Journal
          The EMBO Journal
          EMBO J.
          EMBO
          0261-4189
          1460-2075
          February 01 2018
          February 01 2018
          February 01 2018
          January 12 2018
          : 37
          : 3
          : 367-383
          Article
          10.15252/embj.201797883
          5793801
          29330193
          © 2018

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