The structure of myostatin: follistatin 288: insights into receptor utilization and heparin binding
The structure of myostatin: follistatin 288: insights into receptor utilization and heparin binding
复制标题
DOI：
10.1038/emboj.2009.205
复制
发表时间：
2009-09-02
期刊：
影响因子：
11.4
通讯作者：
Thompson, Thomas B.
中科院分区：
文献类型：
--
作者：
Cash, Jennifer N.;Rejon, Carlis A.;Thompson, Thomas B.
肌生长抑制素是转化生长因子-β（TGF-β）家族的成员，并且是肌肉生长的强负调节剂。在这里，我们提出了与拮抗剂卵泡抑素288（Fst 288）复合的肌肉生长抑制素的晶体结构。我们发现肌生长抑制素的螺旋前区非常类似于TGF-β类成员，并且该区域可以单独交换成激活素A，以通过非经典I型受体Alk 5传递信号。此外，Fst 288的N-末端结构域经历构象重排以结合肌生长抑制素，并且可能充当拮抗剂的特异性位点。此外，当肌肉生长抑制素结合Fst 288时，产生独特的连续正电性表面，这显著增加了对肝素的亲和力。这转化为与细胞表面更强的相互作用，并在Fst 288或Fst 315存在下增强肌肉生长抑制素降解。总体而言，我们已经确定了肌生长抑制素的几个独特特征，这对合理设计可用于治疗肌肉萎缩性疾病的肌生长抑制素抑制剂至关重要。The EMBO Journal（2009）28，2662-2676. doi：10.1038/daj.2009.205;在线发表于2009年7月30日主题分类：信号转导;结构生物学
Myostatin is a member of the transforming growth factor-beta (TGF-beta) family and a strong negative regulator of muscle growth. Here, we present the crystal structure of myostatin in complex with the antagonist follistatin 288 (Fst288). We find that the prehelix region of myostatin very closely resembles that of TGF-beta class members and that this region alone can be swapped into activin A to confer signalling through the non-canonical type I receptor Alk5. Furthermore, the N-terminal domain of Fst288 undergoes conformational rearrangements to bind myostatin and likely acts as a site of specificity for the antagonist. In addition, a unique continuous electropositive surface is created when myostatin binds Fst288, which significantly increases the affinity for heparin. This translates into stronger interactions with the cell surface and enhanced myostatin degradation in the presence of either Fst288 or Fst315. Overall, we have identified several characteristics unique to myostatin that will be paramount to the rational design of myostatin inhibitors that could be used in the treatment of muscle-wasting disorders. The EMBO Journal (2009) 28, 2662-2676. doi: 10.1038/emboj.2009.205; Published online 30 July 2009 Subject Categories: signal transduction; structural biology