o-survival proteins have four (BH1-4) domains; the pro-apoptotic proteins fall into two subgroups, those with more than one BH domain and the BH3-only group. Click, to see more on the domain organization of Bcl-2 family. The pro-survival proteins localize to the outer mitochondrial membrane and to a lesser extent, the ER membrane and nuclear envelope. They act to neutralize the action of pro-apoptotic Bax and Bak1 and prevent the release of cytochrome c (Cycs) from the mitochondrion. Their affinity for Bax and Bak1 varies; the interaction may contribute to sequestration of the two pro-apoptotic proteins. The BH3-only proteins are initiator molecules and two activation models have been proposed. In the direct model, they bind to and activate Bax and Bak1; in the indirect model, they bind to and inactivate the pro-survival proteins. BH3-only proteins bind with high affinity to at least some of the pro-survival members. Active Bax and Bak1 form oligomeric complexes at the mitochondrial membrane and facilitate the release of Cycs from the inter-membrane space [eg. PMID: 16474435, 17322918, 19641503]. In the cytosol, Cycs interacts with Apaf1; in the presence of ATP or dATP they form a heptameric complex - the apoptosome that recruits and activates the initiator caspase Casp9, probably by promoting the formation of the active dimer. The N-terminal CARD domain of Apaf1 recruits Casp9 while the C-terminal WD40 repeats are involved in Cycs binding. The active Casp9 processes and activates the executioner Casp3 and 7; in the extrinsic pathway different initiators activate them [eg. PMID: 17377525, 18931687]. The IAP (Inhibitors of Apoptosis Proteins) family members have one or more BIR domain, many have a RING zinc-finger domain with E3 ubiquitin ligase activity, two have a CARD domain. Xiap/Birc4 inhibits Casp3, 7 and 9; a direct participation of the other members is still debated and indirect mechanisms have been postulated. Xiap is antagonized by Diablo/Smac or Htra2/Omi which are released from the mitochondrion along with Cycs. Htra2 is serine protease that both disrupts Xiap-caspase interaction and degrades Xiap. IAPs are involved in other pathways and processes [eg. PMID: 17573556, 18414036]. A complex bi-directional interplay between caspases and kinases/phosphatases modulates their activities and associated outcomes. Alterations of the apoptotic pathways have been associated with several conditions. To see the ontology report for annotations, GViewer and download, click here
[click to see related KEGG map map04210 and associated entry at Reactome - REACT_964....(less)