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.