title: Crystal structure of full-length Apaf-1: how the death signal is relayed in the mitochondrial pathway of apoptosis.
abstract: The apoptotic protease-activating factor 1 (Apaf-1) relays the death signal in the mitochondrial pathway of apoptosis. Apaf-1 oligomerizes on binding of mitochondrially released cytochrome c into the heptameric apoptosome complex to ignite the downstream cascade of caspases. Here, we present the 3.0 Å crystal structure of full-length murine Apaf-1 in the absence of cytochrome c. The structure shows how the mammalian death switch is kept in its "off" position. By comparing the off state with a recent cryo-electron microscopy derived model of Apaf-1 in its apoptosomal conformation, we depict the molecular events that transform Apaf-1 from autoinhibited monomer to a building block of the caspase-activating apoptosome. Moreover, we have solved the crystal structure of the R265S mutant of full-length murine Apaf-1 in the absence of cytochrome c to 3.55 Å resolution and we show that proper function of Apaf-1 relies on R265 in the vicinity of the bound nucleotide.
authors.affiliation: Insitute for Biophysical Chemistry, Hannover Medical School, OE 4350, D-30625, Hannover, Germany.
authors.forename: Thomas Frank
authors.initials: TF
authors.lastname: Reubold
authors.forename: Sabine
authors.initials: S
authors.lastname: Wohlgemuth
authors.forename: Susanne
authors.initials: S
authors.lastname: Eschenburg
mesh_terms: D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1 / Q000737:chemistry* / Q000235:genetics; D053453:Caspase 9 / Q000737:chemistry; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D057075:Enzyme Assays; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D020125:Mutation, Missense; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D053453:Caspase 9