Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1.
Bcl-x(L), an antiapoptotic Bcl-2 family member, is postulated to function at multiple stages in the cell death pathway. The possibility that Bcl-x(L) inhibits cell death at a late (postmitochondrial) step in the death pathway is supported by this report of a novel apoptosis inhibitor, Aven, which binds to both Bcl-x(L) and the caspase regulator, Apaf-1. Identified in a yeast two-hybrid screen, Aven is broadly expressed and is conserved in other mammalian species. Only those mutants of Bcl-x(L)that retain their antiapoptotic activity are capable of binding Aven. Aven interferes with the ability of Apaf-1 to self-associate, suggesting that Aven impairs Apaf-1-mediated activation of caspases. Consistent with this idea, Aven inhibited the proteolytic activation of caspases in a cell-free extract and suppressed apoptosis induced by Apaf-1 plus caspase-9. Thus, Aven represents a new class of cell death regulator.
Chau
B N
BN
Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Schools of Medicine and Public Health, Baltimore, Maryland 21205, USA.
Cheng
E H
EH
Kerr
D A
DA
Hardwick
J M
JM
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection; D051020:bcl-X Protein
C506592:APAF1 protein, human; C412506:AVEN protein, human; D048868:Adaptor Proteins, Signal Transducing; C506593:Apaf1 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D008565:Membrane Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases