Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction

Hegde, Ramesh, Srinivasula, Srinivasa M., Zhang, ZhiJia, Wassell, Richard, Mukattash, Rula, Cilenti, Lucia, DuBois, Garrett, Lazebnik, Yuri, Zervos, Antonis S., Fernandes-Alnemri, Teresa, Alnemri, Emad S. (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. Journal of Biological Chemistry, 277 (1). pp. 432-438. ISSN 0021-9258

URL: http://www.ncbi.nlm.nih.gov/pubmed/11606597
DOI: 10.1074/jbc.M109721200

Abstract

To identify human proteins that bind to the Smac and caspase-9 binding pocket on the baculoviral inhibitor of apoptosis protein (IAP) repeat 3 (BIR3) domain of human XIAP, we used BIR3 as an affinity reagent, followed by elution with the BIR3 binding peptide AVPIA, microsequencing, and mass spectrometry. The mature serine protease Omi (also known as HtrA2) was identified as a mitochondrial direct BIR3-binding protein and a caspase activator. Like mature Smac (also known as Diablo), mature Omi contains a conserved IAP-binding motif (AVPS) at its N terminus, which is exposed after processing of its N-terminal mitochondrial targeting sequence upon import into the mitochondria. Mature Omi is released together with mature Smac from the mitochondria into the cytosol upon disruption of the outer mitochondrial membrane during apoptosis. Finally, mature Omi can induce apoptosis in human cells in a caspase-independent manner through its protease activity and in a caspase-dependent manner via its ability to disrupt caspase-IAP interaction. Our results provide clear evidence for the involvement of a mitochondrial serine protease in the apoptotic pathway, emphasizing the critical role of the mitochondria in cell death.

Item Type: Paper
Uncontrolled Keywords: Amino Acid Sequence Apoptosis Caspases Humans Inhibitor of Apoptosis Proteins Insect Proteins Mitochondria Mitochondrial Proteins Molecular Sequence Data Proteins Serine Endopeptidases
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > organelles, types and functions > mitochondria
organs, tissues, organelles, cell types and functions > organelles, types and functions
CSHL Authors:
Communities: CSHL labs > Labeznik lab
Depositing User: Matt Covey
Date: 2002
Date Deposited: 12 Dec 2012 17:29
Last Modified: 12 Dec 2012 17:29
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26384

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