title: Crystal structure and mutagenic analysis of the inhibitor-of-apoptosis protein survivin.
abstract: The coupling of apoptosis (programmed cell death) to the cell division cycle is essential for homeostasis and genomic integrity. Here, we report the crystal structure of survivin, an inhibitor of apoptosis, which has been implicated in both control of cell death and regulation of cell division. In addition to a conserved N-terminal Zn finger baculovirus IAP repeat, survivin forms a dimer through a symmetric interaction with an intermolecularly bound Zn atom located along the molecular dyad axis. The interaction of the dimer-related C-terminal alpha helices forms an extended surface of approximately 70 A in length. Mutagenesis analysis revealed that survivin dimerization and an extended negatively charged surface surrounding Asp-71 are required to counteract apoptosis and preserve ploidy. These findings may provide a structural basis for a dual role of survivin in inhibition of apoptosis and regulation of cell division.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA. steve.w.muchmore@abbott.com
authors.forename: S W
authors.initials: SW
authors.lastname: Muchmore
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: C
authors.initials: C
authors.lastname: Jakob
authors.forename: D
authors.initials: D
authors.lastname: Zakula
authors.forename: E D
authors.initials: ED
authors.lastname: Matayoshi
authors.forename: W
authors.initials: W
authors.lastname: Wu
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.forename: S C
authors.initials: SC
authors.lastname: Ng
authors.forename: D C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D017931:DNA Primers / Q000235:genetics; D019281:Dimerization; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D000077022:Survivin; D015032:Zinc / Q000737:chemistry
chemical_list: C107489:BIRC5 protein, human; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D000077022:Survivin; D015032:Zinc