title: Alternative binding modes identified for growth and differentiation factor-associated serum protein (GASP) family antagonism of myostatin.
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.
authors: From the Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267 and.
authors: Ryan G
authors: RG
authors: Walker
authors: From the Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267 and.
authors: Elizabeth B
authors: EB
authors: Angerman
authors: From the Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267 and.
authors: Chandramohan
authors: C
authors: Kattamuri
authors: the Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors: Yun-Sil
authors: YS
authors: Lee
authors: the Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors: Se-Jin
authors: SJ
authors: Lee
authors: From the Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267 and tom.thompson@uc.edu.
authors: Thomas B
authors: TB
authors: Thompson
mesh_terms: D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002850:Chromatography, Gel; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D055435:Myostatin / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012542:Scattering, Radiation; D020349:Surface Plasmon Resonance; D014461:Ultracentrifugation
chemical_list: D002352:Carrier Proteins; C479636:Gprasp1 protein, mouse; C485065:Gprasp2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D055435:Myostatin; D043562:Receptors, G-Protein-Coupled
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
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