5NXS

Crystal Structure of Human Pro-myostatin Precursor at 4.2 A Resolution with Experimental Phases from SeMet labelling

5NXS の概要

• エントリーDOI: 10.2210/pdb5nxs/pdb
• 分子名称: Growth/differentiation factor 8 (1 entity in total)
• 機能のキーワード: growth factor, signaling protein, tgfbeta family, cystine knot
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted : O14793
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76995.85

構造登録者

Cotton, T.R.,Fischer, G.,Hyvonen, M. (登録日: 2017-05-10, 公開日: 2018-01-17, 最終更新日: 2024-11-06)

主引用文献

Cotton, T.R.,Fischer, G.,Wang, X.,McCoy, J.C.,Czepnik, M.,Thompson, T.B.,Hyvonen, M.
Structure of the human myostatin precursor and determinants of growth factor latency.
EMBO J., 37:367-383, 2018

PubMed 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.

PubMed: 29330193
DOI: 10.15252/embj.201797883

実験手法

X-RAY DIFFRACTION (4.19 Å)