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