Apoptosis regulator proteins of the Bcl-2 family, named after B-cell lymphoma 2. This alignment model spans what have been described as Bcl-2 homology regions BH1, BH2, BH3, and BH4. Many members of this family have an additional C-terminal transmembrane segment. Some homologous proteins, which are not included in this model, may miss either the BH4 (Bax, Bak) or the BH2 (Bcl-X(S)) region, and some appear to only share the BH3 region (Bik, Bim, Bad, Bid, Egl-1). This family is involved in the regulation of the outer mitochondrial membrane's permeability and in promoting or preventing the release of apoptogenic factors, which in turn may trigger apoptosis by activating caspases. Bcl-2 and the closely related Bcl-X(L) are anti-apoptotic key regulators of programmed cell death. They are assumed to function via heterodimeric protein-protein interactions, binding pro-apoptotic proteins such as Bad (BCL2-antagonist of cell death), Bid, and Bim, by specifically interacting with their BH3 regions. Interfering with this heterodimeric interaction via small-molecule inhibitors may prove effective in targeting various cancers. This family also includes the Caenorhabditis elegans Bcl-2 homolog CED-9, which binds to CED-4, the C. Elegans homolog of mammalian Apaf-1. Apaf-1, however, does not seem to be inhibited by Bcl-2 directly.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612149804    1 MIAAVDTD--SPREVFFRVAADMFSDGnFNWGRVVALFYFASKLVLKALCTKVPELIRTIMGWTLDFLRERLLGWIQDQG 78
Cdd:TIGR00865  89 MTSQLHITpfTARQSFFQVAAELFRDG-VNWGRIVAFFSFGGALCVESVNKEMSELVSRIAGWMTEYLNEHLHPWIQENG 167

                          90
                  ....*....|....*.
gi 612149804   79 GWVRLLKPPHPHHRAL 94
Cdd:TIGR00865 168 GWDGFVELYGNNAAQL 183

apoptosis regulator; The Bcl-2 (Bcl-2) Family (TC 1.A.21) The Bcl-2 family consists of the apoptosis regulator, Bcl-X, and its homologues. Bcl-X is a dominant regulator of programmed cell death in mammalian cells. The long form (Bcl-X(L)) displays cell death repressor activity, but the short isoform (Bcl-X(S)) and the b-isoform (Bcl-Xb) promote cell death. Bcl-X(L), Bcl-X(S) and Bcl-Xb are three isoforms derived by alternative RNA splicing. Bcl-X(S) forms heterodimers with Bcl-2. Homologues of Bcl-X include the Bax (rat; 192 aas; spQ63690) and Bak (mouse; 208 aas; spO08734) proteins which also influence apoptosis. Using isolated mitochondria, recombinant Bax and Bak have been shown to induce Dy loss, swelling and cytochrome c release. All of these changes are dependent on Ca2+ and are prevented by cyclosporin A and bongkrekic acid, both of which are known to close permeability transition pores (megachannels). Coimmimoprecipitation studies revealed that Bax and Bak interact with VDAC to form permeability transition pores. Thus, even though they can form channels in artificial membranes at acidic pH, proapoptotic Bcl-2 family proteins (including Bax and Bak) probably induce the mitochondrial permeability transition and cytochrome c release by interacting with permeability transition pores, the most important component for pore fomation of which is VDAC. [Regulatory functions, Other]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612149804    1 MIAAVDTD--SPREVFFRVAADMFSDGnFNWGRVVALFYFASKLVLKALCTKVPELIRTIMGWTLDFLRERLLGWIQDQG 78
Cdd:TIGR00865  89 MTSQLHITpfTARQSFFQVAAELFRDG-VNWGRIVAFFSFGGALCVESVNKEMSELVSRIAGWMTEYLNEHLHPWIQENG 167

                          90
                  ....*....|....*.
gi 612149804   79 GWVRLLKPPHPHHRAL 94
Cdd:TIGR00865 168 GWDGFVELYGNNAAQL 183

BCL (B-Cell lymphoma); contains BH1, BH2 regions; (BH1, BH2, (BH3 (one helix only)) and not BH4(one helix only)). Involved in apoptosis regulation

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 612149804     5 VDTDSPREVFFRVAADMFSDGNFNWGRVVALFYFASKLVLKALCTKVPELIRTIMGWTLDFLRERLLGWIQDQGGW 80
Cdd:smart00337  25 VTPGTAIELFGEVATELFSDGNINWGRVVALLSFGGALAVKLVQKEDPDLVSRLASWLSEFLRETLRSWIRENGGW 100

apoptosis regulator; The Bcl-2 (Bcl-2) Family (TC 1.A.21) The Bcl-2 family consists of the apoptosis regulator, Bcl-X, and its homologues. Bcl-X is a dominant regulator of programmed cell death in mammalian cells. The long form (Bcl-X(L)) displays cell death repressor activity, but the short isoform (Bcl-X(S)) and the b-isoform (Bcl-Xb) promote cell death. Bcl-X(L), Bcl-X(S) and Bcl-Xb are three isoforms derived by alternative RNA splicing. Bcl-X(S) forms heterodimers with Bcl-2. Homologues of Bcl-X include the Bax (rat; 192 aas; spQ63690) and Bak (mouse; 208 aas; spO08734) proteins which also influence apoptosis. Using isolated mitochondria, recombinant Bax and Bak have been shown to induce Dy loss, swelling and cytochrome c release. All of these changes are dependent on Ca2+ and are prevented by cyclosporin A and bongkrekic acid, both of which are known to close permeability transition pores (megachannels). Coimmimoprecipitation studies revealed that Bax and Bak interact with VDAC to form permeability transition pores. Thus, even though they can form channels in artificial membranes at acidic pH, proapoptotic Bcl-2 family proteins (including Bax and Bak) probably induce the mitochondrial permeability transition and cytochrome c release by interacting with permeability transition pores, the most important component for pore fomation of which is VDAC. [Regulatory functions, Other]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612149804    1 MIAAVDTD--SPREVFFRVAADMFSDGnFNWGRVVALFYFASKLVLKALCTKVPELIRTIMGWTLDFLRERLLGWIQDQG 78
Cdd:TIGR00865  89 MTSQLHITpfTARQSFFQVAAELFRDG-VNWGRIVAFFSFGGALCVESVNKEMSELVSRIAGWMTEYLNEHLHPWIQENG 167

                          90
                  ....*....|....*.
gi 612149804   79 GWVRLLKPPHPHHRAL 94
Cdd:TIGR00865 168 GWDGFVELYGNNAAQL 183

BCL (B-Cell lymphoma); contains BH1, BH2 regions; (BH1, BH2, (BH3 (one helix only)) and not BH4(one helix only)). Involved in apoptosis regulation

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 612149804     5 VDTDSPREVFFRVAADMFSDGNFNWGRVVALFYFASKLVLKALCTKVPELIRTIMGWTLDFLRERLLGWIQDQGGW 80
Cdd:smart00337  25 VTPGTAIELFGEVATELFSDGNINWGRVVALLSFGGALAVKLVQKEDPDLVSRLASWLSEFLRETLRSWIRENGGW 100