NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP

Chaohong Sun, Mengli Cai, Angelo H. Gunasekera, Robert P. Meadows, Hong Wang, Jun Chen, Haichao Zhang, Wei Wu, Nan Xu, Shi-Chung Ng and Stephen W. Fesik ()
Additional contact information
Chaohong Sun: Abbott Laboratories
Mengli Cai: Abbott Laboratories
Angelo H. Gunasekera: Abbott Laboratories
Robert P. Meadows: Abbott Laboratories
Hong Wang: Abbott Laboratories
Jun Chen: Abbott Laboratories
Haichao Zhang: Abbott Laboratories
Wei Wu: Abbott Laboratories
Nan Xu: Abbott Laboratories
Shi-Chung Ng: Abbott Laboratories
Stephen W. Fesik: Abbott Laboratories

Nature, 1999, vol. 401, issue 6755, 818-822

Abstract: 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.

Date: 1999
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DOI: 10.1038/44617

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