Authors

S. Gupta; R. Singh; P. Datta; Z. J. Zhang; C. Orr; Z. X. Lu; G. DuBois; A. S. Zervos; M. H. Meisler; S. M. Srinivasula; T. Fernandes-Alnemri;E. S. Alnemri

Comments

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

FAMILIAL ALZHEIMERS-DISEASE; NMDA RECEPTOR SUBUNITS; SERINE-PROTEASE; PDZ DOMAINS; MISSENSE MUTATIONS; APOPTOSIS PROTEINS; MULTIPLE MEMBERS; SODIUM-CHANNELS; HTRA FAMILY; CELL-DEATH; Biochemistry & Molecular Biology

Abstract

Presenilin mutations are responsible for most cases of autosomal dominant inherited forms of early onset Alzheimer disease. Presenilins play an important role in amyloid beta-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 beta-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.

Journal Title

Journal of Biological Chemistry

Volume

279

Issue/Number

44

Publication Date

1-1-2004

Document Type

Article

Language

English

First Page

45844

Last Page

45854

WOS Identifier

WOS:000224694900069

ISSN

0021-9258

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