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J. Biol. Chem., Vol. 283, Issue 47, 32831-32838, November 21, 2008

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The Structure of FSTL3·Activin A Complex

DIFFERENTIAL BINDING OF N-TERMINAL DOMAINS INFLUENCES FOLLISTATIN-TYPE ANTAGONIST SPECIFICITY^*

Robin Stamler, Henry T. Keutmann, Yisrael Sidis^¶, Chandramohan Kattamuri, Alan Schneyer^||, and Thomas B. Thompson¹

From the Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati Medical Sciences Building, Cincinnati, Ohio 45267, the Endocrine Unit and the ^¶Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, and the ^||Pioneer Valley Life Science Institute, Baystate Medical Center, Springfield, Massachusetts 01107

Transforming growth factor β family ligands are neutralized by a number of structurally divergent antagonists. Follistatin-type antagonists, which include splice variants of follistatin (FS288 and FS315) and follistatin-like 3 (FSTL3), have high affinity for activin A but differ in their affinity for other ligands, particularly bone morphogenetic proteins. To understand the structural basis for ligand specificity within FS-type antagonists, we determined the x-ray structure of activin A in complex with FSTL3 to a resolution of 2.5 Å. Similar to the previously resolved FS·activin A structures, the ligand is encircled by two antagonist molecules blocking all ligand receptor-binding sites. Recently, the significance of the FS N-terminal domain interaction at the ligand type I receptor site has been questioned; however, our data show that for FSTL3, the N-terminal domain forms a more intimate contact with activin A, implying that this interaction is stronger than that for FS. Furthermore, binding studies revealed that replacing the FSTL3 N-terminal domain with the corresponding FS domain considerably lowers activin A affinity. Therefore, both structural and biochemical evidence support a significant interaction of the N-terminal domain of FSTL3 with activin A. In addition, structural comparisons with bone morphogenetic proteins suggest that the interface where the N-terminal domain binds may be the key site for determining FS-type antagonist specificity.

Received for publication, February 15, 2008 , and in revised form, August 20, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM084186 (to T. B. T.) and DK053828 (to H. T. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: Dept. of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati Medical Sciences Bldg., 231 Albert Sabin Way, Cincinnati, OH 45267. Tel.: 513-558-4517; Fax: 513-558-8474; E-mail: tom.thompson{at}ucmail.uc.edu.

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