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

Sun C, Cai M, Gunasekera AH, Meadows RP, Wang H, Chen J, Zhang H, Wu W, Xu N, Ng SC, Fesik SW
Nature. 1999 401 (6755): 818-22

PMID: 10548111 · DOI:10.1038/44617

The inhibitor-of-apoptosis (IAP) family of proteins, originally identified in baculoviruses, regulate programmed cell death in a variety of organisms. IAPs inhibit specific enzymes (caspases) in the death cascade and contain one to three modules of a common 70-amino-acid motif called the BIR domain. 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 beta-sheet and four alpha-helices and resembles a classical zinc finger. 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. 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.

MeSH Terms (20)

Amino Acids Amino Acid Sequence Caspase 3 Caspase Inhibitors Caspases Enzyme Inhibitors Escherichia coli Humans In Vitro Techniques Jurkat Cells Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Nuclear Magnetic Resonance, Biomolecular Protein Conformation Proteins Protein Structure, Tertiary Recombinant Proteins Sequence Homology, Amino Acid X-Linked Inhibitor of Apoptosis Protein

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