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Published 1 April 2002. doi:10.1083/jcb.200108085
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© The Rockefeller University Press, 0021-9525/2002/4/115 $5.00
The Journal of Cell Biology, Volume 157, Number 1, April 1, 2002 115-124

Article

The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3– and caspase 9–interacting sites



John Silke1, Christine J. Hawkins3,4, Paul G. Ekert1, Joanne Chew5, Catherine L. Day2, Miha Pakusch1, Anne M. Verhagen1 and David L. Vaux1

1 The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia
2 Biochemistry Department, University of Otago, Dunedin, New Zealand
3 Department of Haematology and Oncology, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052 Australia.
4 Department of Paediatrics, University of Melbourne, Parkville 3050 Australia
5 Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117609

Address correspondence to John Silke, The Walter and Eliza Hall Institute, c/o Royal Melbourne Hospital Post Office, Victoria 3050, Australia. Tel.: 61-3-9345-2548. Fax: 61-3-9347-0852. E-mail: silke{at}wehi.edu.au

The X-linked mammalian inhibitor of apoptosis protein (XIAP) has been shown to bind several partners. These partners include caspase 3, caspase 9, DIABLO/Smac, HtrA2/Omi, TAB1, the bone morphogenetic protein receptor, and a presumptive E2 ubiquitin-conjugating enzyme. In addition, we show here that XIAP can bind to itself. To determine which of these interactions are required for it to inhibit apoptosis, we generated point mutant XIAP proteins and correlated their ability to bind other proteins with their ability to inhibit apoptosis. {partial}RING point mutants of XIAP were as competent as their full-length counterparts in inhibiting apoptosis, although impaired in their ability to oligomerize with full-length XIAP. Triple point mutants, unable to bind caspase 9, caspase 3, and DIABLO/HtrA2/Omi, were completely ineffectual in inhibiting apoptosis. However, point mutants that had lost the ability to inhibit caspase 9 and caspase 3 but retained the ability to inhibit DIABLO were still able to inhibit apoptosis, demonstrating that IAP antagonism is required for apoptosis to proceed following UV irradiation.

Key Words: XIAP; caspase 9; caspase 3; DIABLO/smac; UV irradiation


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