Thomas Cotton, Gerhard Fischer, Xuelu Wang, Jason McCoy, Magdalena Czepnik, Thomas B. Thompson, Marko Hyvönen
The EMBO Journal (2018) 37: 367-383 
DOI: 10.15252/embj.201797883
Pre-publication in BiorXiv, DOI: doi.org/10.1101/153403
PDB coordinates: 5NTU (3D view ), 5NXS (3D view )
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 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-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.