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J. Biol. Chem., Vol. 282, Issue 21, 15341-15348, May 25, 2007

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The Bcl-2 Regulator FKBP38-Calmodulin-Ca²⁺ Is Inhibited by Hsp90^*

From the Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle/Saale, Germany

FKBP38 is a negative effector of the anti-apoptotic Bcl-2 protein in neuroblastoma cells. The interaction with Bcl-2 and the enzyme activity of FKBP38 depend on prior binding of calmodulin-Ca²⁺ (CaM-Ca²⁺) at high Ca²⁺ concentrations. The FKBP38 protein structure contains three tetratricopeptide repeat (TPR) motifs corresponding to the Hsp90 interaction sites of other immunophilins. In this study we show that the TPR domain of FKBP38 interacts with the C-terminal domain of Hsp90, but only if the FKBP38-CaM-Ca²⁺ complex is preformed. Hence, FKBP38 is the first example of a TPR-containing immunophilin that interacts cofactor-dependently with Hsp90. In the ternary Hsp90-FKBP38-CaM-Ca²⁺ complex the active site of FKBP38 is blocked, thus preventing interactions with Bcl-2. The dual control of the active site cleft of FKBP38 by CaM-Ca²⁺ and Hsp90 highlights the importance of the enzyme activity of the FKBP38-CaM-Ca²⁺ complex in the regulation of programmed cell death.

Received for publication, December 19, 2006 , and in revised form, February 26, 2007.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 604. 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. 1–5.

¹ To whom correspondence should be addressed. Tel.: 345-55-22800; Fax: 345-55-11972; E-mail: fischer{at}enzyme-halle.mpg.de.

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