Article
- The EMBO Journal (2005) 24, 645 - 655
- doi:10.1038/sj.emboj.7600544
Published online: 13 January 2005
Subject Category:
XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs
Fiona L Scott, Jean-Bernard Denault, Stefan J Riedla, Hwain Shinb, Martin Renatusc and Guy S Salvesen
- Program in Apoptosis and Cell Death Research, The Burnham Institute, La Jolla, CA, USA
Correspondence to:
Guy S Salvesen, Program for Apoptosis & Cell Death, The Burnham Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA. Tel.: +1 858 646 3114; Fax: +1 858 713 6274; E-mail: gsalvesen@burnham.org
aPresent address: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA
bPresent address: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland
cPresent address: Novartis Pharma AG, Postfach, 4002 Basel, Switzerland
Received 24 October 2003; Accepted 10 December 2004
Abstract
The X-linked inhibitor of apoptosis protein (XIAP) uses its second baculovirus IAP repeat domain (BIR2) to inhibit the apoptotic executioner caspase-3 and -7. Structural studies have demonstrated that it is not the BIR2 domain itself but a segment N-terminal to it that directly targets the activity of these caspases. These studies failed to demonstrate a role of the BIR2 domain in inhibition. We used site-directed mutagenesis of BIR2 and its linker to determine the mechanism of executioner caspase inhibition by XIAP. We show that the BIR2 domain contributes substantially to inhibition of executioner caspases. A surface groove on BIR2, which also binds to Smac/DIABLO, interacts with a neoepitope generated at the N-terminus of the caspase small subunit following activation. Therefore, BIR2 uses a two-site interaction mechanism to achieve high specificity and potency for inhibition. Moreover, for caspase-7, the precise location of the activating cleavage is critical for subsequent inhibition. Since apical caspases utilize this cleavage site differently, we predict that the origin of the death stimulus should dictate the efficiency of inhibition by XIAP.
Keywords:
- apoptosis,
- BIR domain,
- caspase,
- IAP,
- protease
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