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J. Biol. Chem., Vol. 282, Issue 21, 15930-15939, May 25, 2007

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Structural and Biophysical Coupling of Heparin and Activin Binding to Follistatin Isoform Functions^*

Thomas F. Lerch¹, Shunichi Shimasaki, Teresa K. Woodruff^¶, and Theodore S. Jardetzky²

From the Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois 60208, the Department of Reproductive Medicine, University of California San Diego School of Medicine, La Jolla, California 92093, and the ^¶Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Follistatin (FS) regulates transforming growth factor- superfamily ligands and is necessary for normal embryonic and ovarian follicle development. Follistatin is expressed as two splice variants (FS288 and FS315). Previous studies indicated differences in heparin binding between FS288 and FS315, potentially influencing the physiological functions and locations of these isoforms. We have determined the structure of the FS315-activin A complex and quantitatively compared heparin binding by the two isoforms. The FS315 complex structure shows that both isoforms inhibit activin similarly, but FS315 exhibits movements within follistatin domain 3 (FSD3) apparently linked to binding of the C-terminal extension. Surprisingly, the binding affinities of FS288 and FS315 for heparin are similar at lower ionic strengths with FS315 binding decreasing more sharply as a function of salt concentration. When bound to activin, FS315 binds heparin similarly to the FS288 isoform, consistent with the structure of the complex, in which the acidic residues of the C-terminal extension cannot interact with the heparin-binding site. Activin-induced binding of heparin is unique to the FS315 isoform and may stimulate clearance of FS315 complexes.

Received for publication, January 25, 2007 , and in revised form, March 22, 2007.

The atomic coordinates and structure factors (code 2P6A) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by National Institutes of Health Grant U54 HD041857 (to T. K. W. and T. S. J.). 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 Supported by Cellular and Molecular Basis for Disease Training Grant T32 GM008061.

² To whom correspondence should be addressed: Dept. of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Cook Hall, Rm. 4133, 2205 Tech Drive, Evanston, IL 60208. Tel.: 847-467-4048; Fax: 847-467-1380; E-mail: tedj{at}northwestern.edu.

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