Alternative binding modes identified for growth and differentiation factor-associated serum protein (GASP) family antagonism of myostatin.
Alternative binding modes identified for growth and differentiation factor-associated serum protein (GASP) family antagonism of myostatin.
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确定了生长和分化因子相关血清蛋白 (GASP) 家族拮抗肌生长抑制素的替代结合模式。
DOI：
10.1074/jbc.m114.624130
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Thompson,ThomasB
中科院分区：
文献类型：
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作者：
Walker,RyanG;Angerman,ElizabethB;Kattamuri,Chandramohan;Lee,Yun-Sil;Lee,Se-Jin;Thompson,ThomasB
肌生长抑制素是TGF-β配体家族的成员，是肌肉生长的强负调节剂。因此，它是肌肉萎缩症的主要治疗靶点。与其他TGF-β家族配体类似，肌肉生长抑制素通过结合多种结构上不同的拮抗剂之一而被中和。包括拮抗剂GASP-1和GASP-2，其独特之处在于它们特异性拮抗肌生长抑制素。然而，很少有人知道从结构的角度来描述GASP拮抗剂与肌生长抑制素的相互作用。在这里，我们提出了GASP-1和GASP-2的肌生长抑制素游离和肌生长抑制素结合状态的第一低分辨率溶液结构。我们的研究已经揭示了GASP-1，其比GASP-2强100倍，优先以不对称的1：1复合物结合肌肉生长抑制素，而GASP-2以对称的2：1复合物结合。此外，GASP-1的C-末端截短导致形成2：1复合物的较低效力的肌肉生长抑制素抑制剂，表明GASP-1的C-末端结构域是不对称复合物形成的主要介质。总的来说，这项研究提供了一个新的视角TGF-β拮抗作用，密切相关的拮抗剂可以利用不同的配体结合策略。
Myostatin, a member of the TGF-β family of ligands, is a strong negative regulator of muscle growth. As such, it is a prime therapeutic target for muscle wasting disorders. Similar to other TGF-β family ligands, myostatin is neutralized by binding one of a number of structurally diverse antagonists. Included are the antagonists GASP-1 and GASP-2, which are unique in that they specifically antagonize myostatin. However, little is known from a structural standpoint describing the interactions of GASP antagonists with myostatin. Here, we present the First low resolution solution structure of myostatin-free and myostatin-bound states of GASP-1 and GASP-2. Our studies have revealed GASP-1, which is 100 times more potent than GASP-2, preferentially binds myostatin in an asymmetrical 1:1 complex, whereas GASP-2 binds in a symmetrical 2:1 complex. Additionally, C-terminal truncations of GASP-1 result in less potent myostatin inhibitors that form a 2:1 complex, suggesting that the C-terminal domains of GASP-1 are the primary mediators for asymmetric complex formation. Overall, this study provides a new perspective on TGF-β antagonism, where closely related antagonists can utilize different ligand-binding strategies.