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J. Biol. Chem., Vol. 282, Issue 42, 30718-30727, October 19, 2007

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A Dimeric Smac/Diablo Peptide Directly Relieves Caspase-3 Inhibition by XIAP

DYNAMIC AND COOPERATIVE REGULATION OF XIAP BY SMAC/DIABLO^*

Zhonghua Gao, Yuan Tian^¶, Junru Wang, Qian Yin^||, Hao Wu^||, Yue-Ming Li^¶, and Xuejun Jiang¹

From the Cell Biology Program and the ^¶Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 and the Graduate School of Biomedical Sciences and the ^||Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021

Caspase activation, the executing event of apoptosis, is under deliberate regulation. IAP proteins inhibit caspase activity, whereas Smac/Diablo antagonizes IAP. XIAP, a ubiquitous IAP, can inhibit both caspase-9, the initiator caspase of the mitochondrial apoptotic pathway, and the downstream effector caspases, caspase-3 and caspase-7. Smac neutralizes XIAP inhibition of caspase-9 by competing for binding of the BIR3 domain of XIAP with caspase-9, whereas how Smac liberates effector caspases from XIAP inhibition is not clear. It is generally believed that binding of Smac with IAP generates a steric hindrance that prevents XIAP from inhibiting effector caspases, and therefore small molecule mimics of Smac are not able to reverse inhibition of the effector caspases. Surprisingly, we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP. Further, we defined the dynamic and cooperative interaction of Smac with XIAP: binding of Smac with the BIR3 domain anchors the subsequent binding of Smac with the BIR2 domain, which in turn attenuates the caspase-3 inhibitory function of XIAP. We also show that XIAP homotrimerizes via its C-terminal Ring domain, making its inhibitory activity toward caspase-3 more susceptible to Smac.

Received for publication, June 27, 2007 , and in revised form, August 14, 2007.

^* This work was supported by National Institutes of Health Grants R01 AI045937 (to H. W.),R01 AG026660 (to Y.-M. L.), and R01 CA113890 (to X. J.), the Goodwin Experimental Therapeutic Center Fund (to Y.-M. L. and X. J.), an Alzheimer's Association Zenith Fellows Award (to Y.-M. L.), and funds from the American Health Assistance Foundation (to Y.-M. L.). 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: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 522, New York, NY 10021. Tel.: 212-639-6814; E-mail: jiangx{at}mskcc.org.

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