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Structure of the human myostatin precursor and determinants of growth factor latency
- Publication Year :
- 2018
- Publisher :
- EMBO, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Follistatin
Proteolysis
medicine.medical_treatment
Regulator
Myostatin
Cleavage (embryo)
Crystallography, X-Ray
General Biochemistry, Genetics and Molecular Biology
Protein Structure, Secondary
Cell Line
03 medical and health sciences
0302 clinical medicine
Transforming Growth Factor beta
medicine
Missense mutation
Humans
Protein Precursors
Muscle, Skeletal
Molecular Biology
Furin
latency
Polymorphism, Genetic
General Immunology and Microbiology
biology
medicine.diagnostic_test
General Neuroscience
Growth factor
pro‐domain
Articles
GDF8
musculoskeletal system
TGF‐β superfamily
Cell biology
Enzyme Activation
030104 developmental biology
HEK293 Cells
Biochemistry
030220 oncology & carcinogenesis
biology.protein
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....5e16cf25bfd882626efad1b91fbfc266