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

DOI: 10.15252/embj.201797883

Authors: Thomas R. Cotton (University of Cambridge) , Gerhard Fischer (University of Cambridge) , Xuelu Wang (University of Cambridge) , Jason C. Mccoy (University of Cincinnati) , Magdalena Czepnik (University of Cincinnati) , Thomas B Thompson (University of Cincinnati) , Marko Hyvonen (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal

State: Published (Approved)
Published: January 2018
Diamond Proposal Number(s): 14043

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.

Journal Keywords: GDF8; latency; myostatin; pro-domain; TGF-b superfamily

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: Soleil; ESRF

Added On: 17/01/2018 10:30

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)