科研之友
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摘要
Background: GASP-1 and GASP-2 are highly specific antagonists for the TGF- ligand myostatin, a negative regulator of muscle growth. Results: GASP-1 and GASP-2 form asymmetric and symmetric complexes with myostatin, respectively. Conclusion: Despite the different binding modes, the GASP proteins retain a high specificity for myostatin. Significance: Inhibition of myostatin can be achieved using different binding modes and may facilitate future development of novel anti-myostatin therapeutics. Myostatin, a member of the TGF- 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- 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- antagonism, where closely related antagonists can utilize different ligand-binding strategies.
- 出版日期2015-3-20
