title: The Apaf-1 apoptosome: a large caspase-activating complex.
abstract: It is increasingly recognized that many key biological processes, including apoptosis, are carried out within very large multi-protein complexes. Apoptosis can be initiated by activation of death receptors or perturbation of the mitochondria causing the release of apoptogenic proteins, which result in the activation of caspases which are responsible for most of the biochemical and morphological changes observed during apoptosis. Caspases are normally inactive and require proteolytic processing for activity and this is achieved by the formation of large protein complexes known as the DISC (death inducing signalling complex) and the apoptosome. In the case of the latter complex, the central scaffold protein is a mammalian CED-4 homologue known as Apaf-1. This is an approximately 130 kDa protein, which in the presence of cytochrome c and dATP oligomerizes to form a very large (approximately 700-1400 kDa) apoptosome complex. The apoptosome recruits and processes caspase-9 to form a holoenzyme complex, which in turn recruits and activates the effector caspases. The apoptosome has been described in cells undergoing apoptosis, in dATP activated cell lysates and in reconstitution studies with recombinant proteins. Recent studies show that formation and function of the apoptosome can be regulated by a variety of factors including intracellular levels of K(+), inhibitor of apoptosis proteins (IAPs), heat shock proteins and Smac/Diablo. These various factors thus ensure that the apoptosome complex is only fully assembled and functional when the cell is irrevocably destined to die.
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK. kc5@le.ac.uk
authors.forename: Kelvin
authors.initials: K
authors.lastname: Cain
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Bratton
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000502:physiology; D003574:Cytochrome c Group / Q000502:physiology; D005420:Flavoproteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000502:physiology; D011188:Potassium / Q000494:pharmacology
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D003574:Cytochrome c Group; D005420:Flavoproteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C120774:aposome; D020169:Caspases; D011188:Potassium