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J. Biol. Chem., Vol. 279, Issue 51, 53126-53135, December 17, 2004

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Reconstitution and Analysis of Soluble Inhibin and Activin Receptor Complexes in a Cell-free System^*

Elisabetta del Re, Yisrael Sidis, David A. Fabrizio, Herbert Y. Lin, and Alan Schneyer¶

From the Program in Membrane Biology and the Renal Unit and the Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Activins and inhibins compose a heterogeneous subfamily within the transforming growth factor- (TGF-) superfamily of growth and differentiation factors with critical biological activities in embryos and adults. They signal through a heteromeric complex of type II, type I, and for inhibin, type III receptors. To characterize the affinity, specificity, and activity of these receptors (alone and in combination) for the inhibin/activin subfamily, we developed a cell-free assay system using soluble receptor-Fc fusion proteins. The soluble activin type II receptor (sActRII)-Fc fusion protein had a 7-fold higher affinity for activin A compared with sActRIIB-Fc, whereas both receptors had a marked preference for activin A over activin B. Although inhibin A and B binding was 20-fold lower compared with activin binding to either type II receptor alone, the mixture of either type II receptor with soluble TGF- type III receptor (TRIII; betaglycan)-Fc reconstituted a soluble high affinity inhibin receptor. In contrast, mixing either soluble activin type II receptor with soluble activin type I receptors did not substantially enhance activin binding. Our results support a cooperative model of binding for the inhibin receptor (ActRII·sTRIII complex) but not for activin receptors (type II + type I) and demonstrate that a complex composed of activin type II receptors and TRIII is both necessary and sufficient for high affinity inhibin binding. This study also illustrates the utility of this cell-free system for investigating hypotheses of receptor complex mechanisms resulting from crystal structure analyses.

Received for publication, July 16, 2004 , and in revised form, September 21, 2004.

^* 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.

^¶ To whom correspondence should be addressed: Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. Tel.: 617-726-5386; Fax: 617-726-5357; E-mail: schneyer.alan{at}mgh.harvard.edu.

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