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Vol. 16, Issue 6, 2926-2933, June 2005

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Mature DIABLO/Smac Is Produced by the IMP Protease Complex on the Mitochondrial Inner Membrane

Lena Burri ^*, Yvan Strahm , Christine J. Hawkins , Ian E. Gentle ^*, Michelle A. Puryer , Anne Verhagen , Bernard Callus , David Vaux , and Trevor Lithgow ^* ||

^* Russell Grimwade School of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia; Victorian Bioinformatics Consortium, Monash University, Clayton, VIC 3800, Australia; Children's Cancer Centre, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3050, Australia; and ^|| Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC 3010, Australia

Submitted December 17, 2004; Revised March 14, 2005; Accepted March 24, 2005
Monitoring Editor: Donald Newmeyer

DIABLO/Smac is a mitochondrial protein that can promote apoptosis by promoting the release and activation of caspases. To do so, DIABLO/Smac must first be processed by a mitochondrial protease and then released into the cytosol, and we show this in an intact cellular system. We propose that the precursor form of DIABLO/Smac enters the mitochondria through a stop-transfer pathway and is processed to its active form by the inner membrane peptidase (IMP) complex. Catalytic subunits of the mammalian IMP complex were identified based on sequence conservation and functional complementation, and the novel sequence motif RX₅P in Imp1 and NX₅S in Imp2 distinguish the two catalytic subunits. DIABLO/Smac is one of only a few specific proteins identified as substrates for the IMP complex in the mitochondrial intermembrane space.

Abbreviations used: IAP, inhibitor of apoptosis protein; IMP, inner membrane peptidase; TIM23, translocase of the inner mitochondrial membrane; TOM, translocase of the outer mitochondrial membrane.

Address correspondence to: Trevor Lithgow (t.lithgow{at}unimelb.edu.au).

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