Department of Biochemistry, University of Cambridge, Cambridge, UK.
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, USA.
EMBO J. 2018 Feb 1;37(3):367-383. doi: 10.15252/embj.201797883. Epub 2018 Jan 12.
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.
肌肉生长抑制素（Myostatin）是脊椎动物肌肉质量的关键调节因子，在肌肉中作为潜伏前体生物合成，并通过前导肽的顺序蛋白水解而被激活。为了研究前肌生长抑制素保持潜伏的分子机制，我们确定了未经处理的前肌生长抑制素的结构，并分析了其不同形式的蛋白质特性。晶体结构和 SAXS 分析表明，前肌生长抑制素采用开放的 V 形结构，具有域交换排列。弗林蛋白酶切割位点切割后，前成熟复合物与成熟生长因子相比，活性显著降低，并保持稳定的复合物状态，对天然拮抗剂卵泡抑素具有抗性。这种潜伏性似乎是由许多不同的特征赋予的，这些特征共同稳定了前域与成熟生长因子的相互作用，从而能够进行调节的逐步激活过程，与典型的前转化生长因子-β1 不同。这些结果为理解前肌生长抑制素中错义突变的影响提供了基础，并为设计新型肌生长抑制素抑制剂铺平了道路。
