Authors

R. Hegde; S. M. Srinivasula; Z. J. Zhang; R. Wassell; R. Mukattash; L. Cilenti; G. DuBois; Y. Lazebnik; A. S. Zervos; T. Fernandes-Alnemri;E. S. Alnemri

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

STRUCTURAL BASIS; CELL-DEATH; IAP; SMAC/DIABLO; DROSOPHILA; ACTIVATION; BINDING; GRIM; HID; Biochemistry & Molecular Biology

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 LAP-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-LAP 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.

Journal Title

Journal of Biological Chemistry

Volume

277

Issue/Number

1

Publication Date

1-1-2002

Document Type

Article

Language

English

First Page

432

Last Page

438

WOS Identifier

WOS:000173087900058

ISSN

0021-9258

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