Autocatalytic processing of HtrA2/Omi is essential for induction of caspase-dependent cell death through antagonizing XIAP

Young Mo Seong, Ju Youn Choi, Hyo Jin Park, Ki-Joong Kim, Sang Gun Ahn, Geun Hye Seong, In Kyung Kim, Seong Man Kang, Hyangshuk Rhim

Research output: Contribution to journalArticle

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Abstract

A mature form of nuclear-encoded mitochondrial serine protease HtrA2/Omi is pivotal in regulating apoptotic cell death; however, the underlying mechanism of the processing event of HtrA2/Omi and its relevant biological function remain to be clarified. Here, we describe that HtrA2/Omi is autocatalytically processed to the 36-kDa protein fragment, which is required for the cytochrome c-dependent caspase activation along with neutralizing XIAP-mediated inhibition of caspases through interaction with XIAP, eventually promoting apoptotic cell death. We have shown that the autocatalytic processing of HtrA2/Omi occurs via an intermolecular event, demonstrated by incubating an in vitro translated HtrA2/Omi (S306A) mutant with the enzymatically active gluatathione S-transferase-HtrA2/Omi protein. Using N-terminal amino acid sequencing and mutational analysis, we identified that the autocatalytic cleavage site is the carbosyl side of alanine 133 of HtrA2/ Omi, resulting in exposure of an inhibitor of apoptosis protein binding motif in its N terminus. Our study provides evidence that the autocatalytic processing of HtrA2/Omi is crucial for regulating HtrA2/Omi-mediated apoptotic cell death.

Original languageEnglish
Pages (from-to)37588-37596
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number36
DOIs
Publication statusPublished - 2004 Sep 3

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Cell death
Caspases
Cell Death
Processing
Inhibitor of Apoptosis Proteins
Amino Acid Motifs
Protein Sequence Analysis
Serine Proteases
Transferases
Cytochromes c
Protein Binding
Alanine
Proteins
Chemical activation
Amino Acids

ASJC Scopus subject areas

  • Biochemistry

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Autocatalytic processing of HtrA2/Omi is essential for induction of caspase-dependent cell death through antagonizing XIAP. / Seong, Young Mo; Choi, Ju Youn; Park, Hyo Jin; Kim, Ki-Joong; Ahn, Sang Gun; Seong, Geun Hye; Kim, In Kyung; Kang, Seong Man; Rhim, Hyangshuk.

In: Journal of Biological Chemistry, Vol. 279, No. 36, 03.09.2004, p. 37588-37596.

Research output: Contribution to journalArticle

Seong, Young Mo ; Choi, Ju Youn ; Park, Hyo Jin ; Kim, Ki-Joong ; Ahn, Sang Gun ; Seong, Geun Hye ; Kim, In Kyung ; Kang, Seong Man ; Rhim, Hyangshuk. / Autocatalytic processing of HtrA2/Omi is essential for induction of caspase-dependent cell death through antagonizing XIAP. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 36. pp. 37588-37596.
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