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J. Biol. Chem., Vol. 279, Issue 44, 45844-45854, October 29, 2004

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The C-terminal Tail of Presenilin Regulates Omi/HtrA2 Protease Activity^*

Sanjeev Gupta, Rajesh Singh, Pinaki Datta, ZhiJia Zhang, Christopher Orr, Zhixian Lu, Garrett DuBois, Antonis S. Zervos¶, Miriam H. Meisler||, Srinivasa M. Srinivasula**, Teresa Fernandes-Alnemri, and Emad S. Alnemri

From the Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, the ^¶Biomolecular Science Center, University of Central Florida, Orlando, Florida 32826, and the ^||Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-0618

Presenilin mutations are responsible for most cases of autosomal dominant inherited forms of early onset Alzheimer disease. Presenilins play an important role in amyloid -precursor processing, NOTCH receptor signaling, and apoptosis. However, the molecular mechanisms by which presenilins regulate apoptosis are not fully understood. Here, we report that presenilin-1 (PS1) regulates the proteolytic activity of the serine protease Omi/HtrA2 through direct interaction with its regulatory PDZ domain. We show that a peptide corresponding to the cytoplasmic C-terminal tail of PS1 dramatically increases the proteolytic activity of Omi/HtrA2 toward the inhibitor of apoptosis proteins and -casein and induces cell death in an Omi/HtrA2-dependent manner. Consistent with these results, ectopic expression of full-length PS1, but not PS1 lacking the C-terminal PDZ binding motif, potentiated Omi/HtrA2-induced cell death. Our results suggest that the C terminus of PS1 is an activation peptide ligand for the PDZ domain of Omi/HtrA2 and may regulate the protease activity of Omi/HtrA2 after its release from the mitochondria during apoptosis. This mechanism of Omi/HtrA2 activation is similar to the mechanism of activation of the related bacterial DegS protease by the outer-membrane porins.

Received for publication, May 4, 2004 , and in revised form, July 23, 2004.

^* This work was supported by National Institutes of Health Grants CA78890, AG14357, and AG13487 (to E. S. A.) and GM24872 (to M. H. M.). 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.

Both authors contributed equally to this work.

^** Sidney Kimmel Scholar.

To whom correspondence should be addressed: Thomas Jefferson University, Kimmel Cancer Institute, Bluemle Life Sciences Bldg., Rm. 904, 233 S 10th St., Philadelphia, PA 19107. Tel.: 215-503-4632; Fax: 215-923-1098; E-mail: E_Alnemri{at}lac.jci.tju.edu .

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