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J. Biol. Chem., Vol. 280, Issue 48, 40177-40186, December 2, 2005

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Structural Basis for a Functional Antagonist in the Transforming Growth Factor Superfamily^*

Robert W. Cook, Thomas B. Thompson, Sudhi P. Kurup, Theodore S. Jardetzky¶1, and Teresa K. Woodruff||**12

From the Departments of Neurobiology and Physiology, Biochemistry, Molecular Biology and Cell Biology, and ^¶Microbiology and Immunology, Northwestern University, Evanston, Illinois 60208, the ^||Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, and the ^**Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611

Within the transforming growth factor superfamily, the agonist-antagonist relationship between activin and inhibin is unique and critical to integrated reproductive function. Activin acts in the pituitary to stimulate follicle-stimulating hormone, and is antagonized by endocrine acting, gonadally derived inhibin. We have undertaken a mutational analysis of the activin A subunit to determine the precise structural aspects that contribute to inhibin antagonism of activin. By substituting specific amino acid residues in the activin A subunit with similarly aligned amino acids from the subunit, we have pinpointed the residues required for activin receptor binding and activity, as well as for inhibin antagonism of activin through its receptors. Additionally, we have identified an activin mutant with a higher affinity for the activin type I receptor that provides structural evidence for the evolution of ligand-receptor interactions within the transforming growth factor superfamily.

Received for publication, April 26, 2005 , and in revised form, August 30, 2005.

^* This work was supported by the Center for Reproductive Research at Northwestern University, National Institutes of Health Grant U54 HD041857, and Reproductive Biology Training Grant T32HD007068. FSH radioimmunoassay was performed at the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core supported by National Institutes of Health NICHD (SCCPRR) Grant U54-HD28934. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked"advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Members of the Northwestern University Robert H. Lurie Comprehensive Cancer Center.

² To whom correspondence should be addressed: Northwestern University, O.T. Hogan4–150, 2205 Tech Dr., Evanston, IL 60208. Tel.: 847-491-2666; Fax: 847-491-2224; E-mail: tkw{at}northwestern.edu.

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