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J. Biol. Chem., Vol. 283, Issue 24, 16743-16751, June 13, 2008

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Suppression of Inhibin A Biological Activity by Alterations in the Binding Site for Betaglycan^*

Yogeshwar Makanji, Kelly L. Walton, Matthew C. Wilce^¶, Karen L. Chan, David M. Robertson, and Craig A. Harrison¹

From the Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia and the Departments of Obstetrics and Gynecology and ^¶Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia

Inhibins A and B negatively regulate the production and secretion of follicle-stimulating hormone from the anterior pituitary, control ovarian follicle development and steroidogenesis, and act as tumor suppressors in the gonads. Inhibins regulate these reproductive events by forming high affinity complexes with betaglycan and activin or bone morphogenetic protein type II receptors. In this study, the binding site of inhibin A for betaglycan was characterized using inhibin A mutant proteins. An epitope for high affinity betaglycan binding was detected spanning the outer convex surface of the inhibin -subunit. Homology modeling indicates that key -subunit residues (Tyr⁵⁰, Val¹⁰⁸, Thr¹¹¹, Ser¹¹², Phe¹¹⁸, Lys¹¹⁹, and Tyr¹²⁰) form a contiguous epitope in this region of the molecule. Disruption of betaglycan binding by the simultaneous substitution of Thr¹¹¹, Ser¹¹², and Tyr¹²⁰ to alanine yielded an inhibin A variant that was unable to suppress activin-induced follicle-stimulating hormone release by rat pituitary cells in culture. Together these results indicate that a high affinity interaction between betaglycan and residues Val¹⁰⁸–Tyr¹²⁰ of the inhibin -subunit mediate inhibin A biological activity.

Received for publication, February 8, 2008 , and in revised form, April 3, 2008.

^* This work was supported by a Monash Postgraduate Scholarship (to Y. M.) and Project CH 388920 and Program Grant DMR 241000 from the National Health and Medical Research Council of Australia. 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 To whom correspondence should be addressed: Prince Henry's Institute of Medical Research, 246 Clayton Rd., Clayton, VIC 3168, Australia. Tel.: 61-3-95947915; Fax: 61-3-95947909; E-mail: craig.harrison{at}princehenrys.org.

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