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J Biol Chem. 2015 Mar 20;290(12):7506-16. doi: 10.1074/jbc.M114.624130. Epub 2015 Feb 5.

Alternative binding modes identified for growth and differentiation factor-associated serum protein (GASP) family antagonism of myostatin.

Author information

1
From the Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267 and.
2
the Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
3
From the Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267 and tom.thompson@uc.edu.

Abstract

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.

KEYWORDS:

Analytical Ultracentrifugation; Growth and Differentiation factor-8 (GDF-8); Growth and Differentiation-associated Serum Protein; Myostatin; Small Angle X-ray Scattering (SAXS); Structural Biology; Transforming Growth Factor Beta (TGF-B); WFIKKN

PMID:
25657005
PMCID:
PMC4367259
DOI:
10.1074/jbc.M114.624130
[Indexed for MEDLINE]
Free PMC Article

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