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

Abstract

The inhibitor-of-apoptosis (IAP) family of proteins, originally identified in baculoviruses¹, regulate programmed cell death in a variety of organisms^2,3,4,5,6. IAPs inhibit specific enzymes (caspases) in the death cascade^7,8,9,10,11 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 IAPs^10,11. 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.