Abstract
The inhibitor-of-apoptosis (IAP) family of proteins, originally identified in baculoviruses1, regulate programmed cell death in a variety of organisms2,3,4,5,6. IAPs inhibit specific enzymes (caspases) in the death cascade7,8,9,10,11 and contain one to three modules of a common 70-amino-acid motif called the BIR domain12. Here we describe the nuclear magnetic resonance structure of a region encompassing the second BIR domain (BIR2) of a human IAP family member, XIAP (also called hILP or MIHA). The structure of the BIR domain consists of a three-stranded antiparallel β-sheet and four α-helices and resembles a classical zinc finger13. Unexpectedly, conserved amino acids within the linker region between the BIR1 and BIR2 domains were found to be critical for inhibiting caspase-3. The absence or presence of these residues may explain the differences in caspase inhibition observed for different truncated and full-length IAPs10,11. Our data further indicate that these residues may bind to the active site and that the BIR domain may interact with an adjacent site on the enzyme.
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Acknowledgements
We thank R. Mendoza for technical assistance; A. Pardi for the starter cultures of Pseudomonas aeruginosa and Pf1 phage; M. Clore for a modified version of the X-PLOR program; F. Delaglio and A. Bax for the TALOS program; and J. Wu from IDUN Pharmaceuticals for the caspase-3 clone.
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Sun, C., Cai, M., Gunasekera, A. et al. NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature 401, 818–822 (1999). https://doi.org/10.1038/44617
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DOI: https://doi.org/10.1038/44617
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