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
ISSN
0021-9258
Recommended Citation
Gupta, Sanjeev; Singh, Rajesh; Datta, Pinaki; Zhang, Zhi-Jia; Orr, Christopher; Lu, Zhixian; DuBois, Garrey; Zervos, Antonis S.; Meisler, Miriam H.; Srinivasula, Srinivasa M.; Fernandes-Alnemri, Teresa; and Alnemri, Emad S., "The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity" (2004). Faculty Bibliography 2000s. 4389.
https://stars.library.ucf.edu/facultybib2000/4389
Comments
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