title: NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP.
abstract: 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.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sun
authors.forename: M
authors.initials: M
authors.lastname: Cai
authors.forename: A H
authors.initials: AH
authors.lastname: Gunasekera
authors.forename: R P
authors.initials: RP
authors.lastname: Meadows
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Wu
authors.forename: N
authors.initials: N
authors.lastname: Xu
authors.forename: S C
authors.initials: SC
authors.lastname: Ng
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D000596:Amino Acids; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D011506:Proteins; D011994:Recombinant Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases