bh3 interacting domain death agonist protein


Summary: A member of the Bcl-2 protein family that reversibly binds MEMBRANES. It is a pro-apoptotic protein that is activated by caspase cleavage.

Top Publications

  1. Clarke P, Beckham J, Leser J, Hoyt C, Tyler K. Fas-mediated apoptotic signaling in the mouse brain following reovirus infection. J Virol. 2009;83:6161-70 pubmed publisher
  2. Coutinho Camillo C, Lourenço S, Nishimoto I, Kowalski L, Soares F. Expression of Bcl-2 family proteins and association with clinicopathological characteristics of oral squamous cell carcinoma. Histopathology. 2010;57:304-16 pubmed publisher
  3. Ku B, Liang C, Jung J, Oh B. Evidence that inhibition of BAX activation by BCL-2 involves its tight and preferential interaction with the BH3 domain of BAX. Cell Res. 2011;21:627-41 pubmed publisher
  4. Varfolomeev E, Alicke B, Elliott J, Zobel K, West K, Wong H, et al. X chromosome-linked inhibitor of apoptosis regulates cell death induction by proapoptotic receptor agonists. J Biol Chem. 2009;284:34553-60 pubmed publisher
  5. Bleicken S, Wagner C, García Sáez A. Mechanistic differences in the membrane activity of Bax and Bcl-xL correlate with their opposing roles in apoptosis. Biophys J. 2013;104:421-31 pubmed publisher
    ..Based on our findings, we propose new models for the mechanisms of action of Bax and Bcl-xL that relate their membrane activity to their opposing roles in apoptosis and beyond. ..
  6. Kazi A, Sun J, Doi K, Sung S, Takahashi Y, Yin H, et al. The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. J Biol Chem. 2011;286:9382-92 pubmed publisher
    ..Finally, BH3-M6 sensitizes cells to apoptosis induced by the proteasome inhibitor CEP-1612. ..
  7. Sinicrope F, Rego R, Okumura K, Foster N, O Connell M, Sargent D, et al. Prognostic impact of bim, puma, and noxa expression in human colon carcinomas. Clin Cancer Res. 2008;14:5810-8 pubmed publisher
    ..Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs. ..
  8. Bird G, Bernal F, Pitter K, Walensky L. Synthesis and biophysical characterization of stabilized alpha-helices of BCL-2 domains. Methods Enzymol. 2008;446:369-86 pubmed publisher
    ..Here we describe the chemical synthesis of Stabilized Alpha-Helices of BCL-2 domains or SAHBs, and the analytical methods used to characterize their secondary structure, proteolytic stability, and cellular penetrance. ..
  9. Engel T, Plesnila N, Prehn J, Henshall D. In vivo contributions of BH3-only proteins to neuronal death following seizures, ischemia, and traumatic brain injury. J Cereb Blood Flow Metab. 2011;31:1196-210 pubmed publisher
    ..Future challenges include evaluating the remaining BH3-only proteins, explaining different causal contributions, and, if possible, exploring neurologic outcomes in mouse models deficient for multiple BH3-only proteins. ..

More Information


  1. Sinicrope F, Rego R, Foster N, Thibodeau S, Alberts S, Windschitl H, et al. Proapoptotic Bad and Bid protein expression predict survival in stages II and III colon cancers. Clin Cancer Res. 2008;14:4128-33 pubmed publisher
    ..If validated, Bad and Bid expression may assist in risk stratification and selection of patients to receive adjuvant chemotherapy. ..
  2. García Sáez A, Ries J, Orzáez M, Perez Paya E, Schwille P. Membrane promotes tBID interaction with BCL(XL). Nat Struct Mol Biol. 2009;16:1178-85 pubmed publisher
    ..Our findings imply an active role of the membrane in modulating the interactions between BCL2 proteins that has so far been underestimated. ..
  3. Gavathiotis E, Suzuki M, Davis M, Pitter K, Bird G, Katz S, et al. BAX activation is initiated at a novel interaction site. Nature. 2008;455:1076-81 pubmed publisher
    ..Thus, we have now defined a BAX interaction site for direct activation, establishing a new target for therapeutic modulation of apoptosis. ..
  4. Quast S, Berger A, Buttstädt N, Friebel K, Schönherr R, Eberle J. General Sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC. PLoS ONE. 2012;7:e39290 pubmed publisher
    ..As both TRAIL and IK1 inhibitors had shown only minor side effects in clinical trials, a clinical application of this combination is conceivable. ..
  5. Kantari C, Walczak H. Caspase-8 and bid: caught in the act between death receptors and mitochondria. Biochim Biophys Acta. 2011;1813:558-63 pubmed publisher
    ..We end our review on an up-to-date discussion of the determinants of the type I-type II cell distinction. This article is part of a Special Issue entitled Mitochondria: the deadly organelle. ..
  6. Zhao K, Zhou H, Zhao X, Wolff D, Tu Y, Liu H, et al. Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis. J Lipid Res. 2012;53:2102-14 pubmed publisher
    ..We further noted that chymotrypsin-cleaved Bid is more potent than tBid at binding to PA, inserting into the lipid bilayer, and promoting LMP. This amplification mechanism likely contributes to the culmination of apoptotic signaling. ..
  7. Du H, Wolf J, Schafer B, Moldoveanu T, Chipuk J, Kuwana T. BH3 domains other than Bim and Bid can directly activate Bax/Bak. J Biol Chem. 2011;286:491-501 pubmed publisher
    ..We propose that, in certain contexts, direct activation by BH3-only proteins other than Bim and Bid may significantly contribute to MOMP and apoptosis. ..
  8. Song G, Chen G, Yun J, Lai P. Association of p53 with Bid induces cell death in response to etoposide treatment in hepatocellular carcinoma. Curr Cancer Drug Targets. 2009;9:871-80 pubmed
    ..These findings reveal a novel mechanism by which p53 is associated with Bid in the nucleus to facilitate exportation of Bid to the mitochondria and induce apoptosis in response to etoposide-induced DNA damage in HCC. ..
  9. Billen L, Shamas Din A, Andrews D. Bid: a Bax-like BH3 protein. Oncogene. 2008;27 Suppl 1:S93-104 pubmed publisher
    ..These findings implicate Bid as a BH3-only protein that is both structurally and functionally related to multi-BH region Bcl-2 family proteins such as Bax. ..
  10. Llambi F, Moldoveanu T, Tait S, Bouchier Hayes L, Temirov J, McCormick L, et al. A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell. 2011;44:517-31 pubmed publisher
    ..Further, MODE 2 sequestration prevents mitochondrial fusion. We provide a unified model of BCL-2 family function that helps to explain otherwise paradoxical observations relating to MOMP, apoptosis, and mitochondrial dynamics. ..
  11. Yamaguchi R, Lartigue L, Perkins G, Scott R, Dixit A, Kushnareva Y, et al. Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell. 2008;31:557-69 pubmed publisher
    ..Thus, apoptosis requires a subtle form of Opa1-dependent crista remodeling that is induced by BH3-only proteins and Bax/Bak but independent of MOMP. ..
  12. Appelqvist H, Johansson A, Linderoth E, Johansson U, Antonsson B, Steinfeld R, et al. Lysosome-mediated apoptosis is associated with cathepsin D-specific processing of bid at Phe24, Trp48, and Phe183. Ann Clin Lab Sci. 2012;42:231-42 pubmed
    ..Our study suggests that cytosolic cathepsin D triggers Bax-mediated cytochrome c release by proteolytic activation of Bid. ..
  13. Spencer S, Gaudet S, Albeck J, Burke J, Sorger P. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature. 2009;459:428-32 pubmed publisher
    ..Our results have implications for understanding 'fractional killing' of tumour cells after exposure to chemotherapy, and for variability in mammalian signal transduction in general. ..
  14. Shelton S, Shawgo M, Robertson J. Cleavage of Bid by executioner caspases mediates feed forward amplification of mitochondrial outer membrane permeabilization during genotoxic stress-induced apoptosis in Jurkat cells. J Biol Chem. 2009;284:11247-55 pubmed publisher
    ..However, the fact that cleavage of Bid to tBid is mediated by executioner caspases suggests that a self-amplifying feed forward loop involving caspases, Bid, and mitochondria may help determine irreversible commitment to apoptosis. ..
  15. Lovell J, Billen L, Bindner S, Shamas Din A, Fradin C, Leber B, et al. Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell. 2008;135:1074-84 pubmed publisher
    ..Bcl-XL prevents membrane-bound tBid from binding Bax. Bad releases tBid from Bcl-XL, restoring both tBid binding to Bax and membrane permeabilization. ..
  16. Choi W, Kim G, Lee W, Choi Y. Sanguinarine, a benzophenanthridine alkaloid, induces apoptosis in MDA-MB-231 human breast carcinoma cells through a reactive oxygen species-mediated mitochondrial pathway. Chemotherapy. 2008;54:279-87 pubmed publisher
    ..Our data imply that sanguinarine-induced ROS are key mediators of MMP collapse, which leads to the release of cytochrome c followed by caspase activation, culminating in apoptosis. ..
  17. Tiwari M, Lopez Cruzan M, Morgan W, Herman B. Loss of caspase-2-dependent apoptosis induces autophagy after mitochondrial oxidative stress in primary cultures of young adult cortical neurons. J Biol Chem. 2011;286:8493-506 pubmed publisher
    ..In summary, the present study identifies a novel function of caspase-2 in mitochondrial oxidative stress-induced apoptosis in neurons cultured from young adult mice. ..
  18. Lin C, Shih W, Lin F, Hsieh Y, Kuo Y, Liao M, et al. Bovine ephemeral fever virus-induced apoptosis requires virus gene expression and activation of Fas and mitochondrial signaling pathway. Apoptosis. 2009;14:864-77 pubmed publisher
    ..Taken together, this study provided first evidence demonstrating that BEFV-induced apoptosis requires viral gene expression and occurs through the activation of Fas and mitochondrion-mediated caspase-dependent pathways. ..
  19. Montessuit S, Somasekharan S, Terrones O, Lucken Ardjomande S, Herzig S, Schwarzenbacher R, et al. Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell. 2010;142:889-901 pubmed publisher
    ..In cells, overexpression of Drp1 R247A/E delays Bax oligomerization and cell death. Our findings uncover a function of Drp1 and provide insight into the mechanism of Bax oligomerization...
  20. Zaltsman Y, Shachnai L, Yivgi Ohana N, Schwarz M, Maryanovich M, Houtkooper R, et al. MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria. Nat Cell Biol. 2010;12:553-562 pubmed publisher
    ..These loss-of-function models indicate that MTCH2/MIMP has a critical function in liver apoptosis by regulating the recruitment of tBID to mitochondria. ..
  21. Wilfling F, Weber A, Potthoff S, Vögtle F, Meisinger C, Paschen S, et al. BH3-only proteins are tail-anchored in the outer mitochondrial membrane and can initiate the activation of Bax. Cell Death Differ. 2012;19:1328-36 pubmed publisher
    ..The recognition of C-terminal membrane-insertion of BH3-only proteins will permit the development of a more detailed concept of the initiation of mitochondrial apoptosis. ..
  22. Moldoveanu T, Grace C, Llambi F, Nourse A, Fitzgerald P, Gehring K, et al. BID-induced structural changes in BAK promote apoptosis. Nat Struct Mol Biol. 2013;20:589-97 pubmed publisher
    ..In contrast, the BH3-only proteins NOXA and BAD are predicted to clash with the trigger site and are not activators of BAK. These findings provide insights into the early stages of BAK activation. ..
  23. Yao Y, Bobkov A, Plesniak L, Marassi F. Mapping the interaction of pro-apoptotic tBID with pro-survival BCL-XL. Biochemistry. 2009;48:8704-11 pubmed publisher
    ..Characterization of the binding thermodynamics by ITC reveals that the interaction between tBID and BCL-XL is driven by enthalpy but disfavored by the entropy associated with the conformational order induced in tBID upon binding BCL-XL. ..
  24. Kaufmann T, Strasser A, Jost P. Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ. 2012;19:42-50 pubmed publisher
  25. Unterkircher T, Cristofanon S, Vellanki S, Nonnenmacher L, Karpel Massler G, Wirtz C, et al. Bortezomib primes glioblastoma, including glioblastoma stem cells, for TRAIL by increasing tBid stability and mitochondrial apoptosis. Clin Cancer Res. 2011;17:4019-30 pubmed publisher
    ..These findings provide compelling evidence that the combination of bortezomib and TRAIL presents a promising novel strategy to trigger cell death in glioblastoma, including glioblastoma stem cells, which warrants further investigation. ..
  26. Oh K, Singh P, Lee K, Foss K, Lee S, Park M, et al. Conformational changes in BAK, a pore-forming proapoptotic Bcl-2 family member, upon membrane insertion and direct evidence for the existence of BH3-BH3 contact interface in BAK homo-oligomers. J Biol Chem. 2010;285:28924-37 pubmed publisher
    ..Detailed analyses of the data provide new insights into the structure of the BAX or BAK homodimer. ..
  27. Aranovich A, Liu Q, Collins T, Geng F, Dixit S, Leber B, et al. Differences in the mechanisms of proapoptotic BH3 proteins binding to Bcl-XL and Bcl-2 quantified in live MCF-7 cells. Mol Cell. 2012;45:754-63 pubmed publisher
    ..Moreover, the BH3 mimetic ABT-737 inhibited Bad and Bid but not Bim binding to Bcl-XL and Bcl-2. Thus, the selectivity of ABT-737 also differs markedly from predictions made from in vitro measurements. ..
  28. Kaufmann T, Jost P, Pellegrini M, Puthalakath H, Gugasyan R, Gerondakis S, et al. Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim. Immunity. 2009;30:56-66 pubmed publisher
    ..These observations identify caspase-8 and the BH3-only proteins Bid and Bim as potential therapeutic targets for treatment of inflammatory liver diseases. ..
  29. Pitter K, Bernal F, LaBelle J, Walensky L. Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains. Methods Enzymol. 2008;446:387-408 pubmed publisher
    ..Here, we describe the in vitro and cell-based methods that exploit SAHB compounds to determine the functional consequences of BH3 interactions in regulating apoptosis. ..
  30. Garcia Perez C, Roy S, Naghdi S, Lin X, Davies E, Hajnoczky G. Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling. Proc Natl Acad Sci U S A. 2012;109:4497-502 pubmed publisher
    ..Thus, Bid engages a ROS-dependent, local intermitochondrial potentiation mechanism that amplifies the apoptotic signal as a wave. ..
  31. Yecies D, Carlson N, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood. 2010;115:3304-13 pubmed publisher
    ..This dynamic increase suggests a novel mechanism whereby modulation of antiapoptotic protein function communicates with nuclear transcriptional machinery. ..
  32. Wong C, Anderson D, Lee E, Fairlie W, Ludlam M. Direct visualization of Bcl-2 family protein interactions using live cell fluorescent protein redistribution assays. Cell Death Dis. 2012;3:e288 pubmed publisher
    ..In addition to the relevance of our assays for drug discovery, we anticipate that our work will contribute to an improved understanding of the mechanisms that regulate these important protein-protein interactions within the cell. ..
  33. Zhang H, Zhong C, Shi L, Guo Y, Fan Z. Granulysin induces cathepsin B release from lysosomes of target tumor cells to attack mitochondria through processing of bid leading to Necroptosis. J Immunol. 2009;182:6993-7000 pubmed publisher
    ..Cathepsin B silencing and Bid or Bax/Bak deficiency resists granulysin-induced cytochrome c and apoptosis-activating factor release and is less susceptible to cytolysis against target tumor cells. ..
  34. Shamas Din A, Bindner S, Zhu W, Zaltsman Y, Campbell C, Gross A, et al. tBid undergoes multiple conformational changes at the membrane required for Bax activation. J Biol Chem. 2013;288:22111-27 pubmed publisher
    ..Thus the interaction of Mtch2 and tBid is a potential target for therapeutic control of Bid initiated cell death. ..
  35. Sheridan C, Delivani P, Cullen S, Martin S. Bax- or Bak-induced mitochondrial fission can be uncoupled from cytochrome C release. Mol Cell. 2008;31:570-85 pubmed publisher
    ..These data suggest that Bax/Bak-initiated remodeling of mitochondrial networks and cytochrome c release are separable events and that Bcl-2 family proteins can influence mitochondrial fission-fusion dynamics independent of apoptosis. ..
  36. Köhler B, Anguissola S, Concannon C, Rehm M, Kogel D, Prehn J. Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands' apoptotic and synergistic effects. PLoS ONE. 2008;3:e2844 pubmed publisher
    ..They also show that the synergistic effects of TRAIL in combination with either ER stressors or genotoxic anti-cancer drugs are nearly exclusively mediated via an increased activation of Bid-induced apoptosis signalling. ..
  37. Sarosiek K, Chi X, Bachman J, Sims J, Montero J, Patel L, et al. BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response. Mol Cell. 2013;51:751-65 pubmed publisher
    ..Therefore, BID and BIM have nonoverlapping roles in the induction of apoptosis via BAK and BAX, affecting chemotherapy response...
  38. Wang Y, Tjandra N. Structural insights of tBid, the caspase-8-activated Bid, and its BH3 domain. J Biol Chem. 2013;288:35840-51 pubmed publisher
    ..Our data provided structural details on the membrane-associated state of tBid and the functional implications of its membrane-associated BH3 domain. ..
  39. Schug Z, Gonzalvez F, Houtkooper R, Vaz F, Gottlieb E. BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ. 2011;18:538-48 pubmed publisher
    ..Our findings indicate that during extrinsic apoptosis, caspase-8 can specifically target BID where it is mostly needed, on the surface of mitochondria. ..
  40. Bleicken S, Classen M, Padmavathi P, Ishikawa T, Zeth K, Steinhoff H, et al. Molecular details of Bax activation, oligomerization, and membrane insertion. J Biol Chem. 2010;285:6636-47 pubmed publisher
  41. Kim H, Tu H, Ren D, Takeuchi O, Jeffers J, Zambetti G, et al. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell. 2009;36:487-99 pubmed publisher
    ..Accordingly, deficiency of Bim/Puma impedes ER stress-induced BAX/BAK activation and apoptosis. Our study provides mechanistic insights regarding the spatiotemporal execution of BAX/BAK-governed cell death. ..
  42. Anguissola S, Köhler B, O Byrne R, Dussmann H, Cannon M, Murray F, et al. Bid and calpains cooperate to trigger oxaliplatin-induced apoptosis of cervical carcinoma HeLa cells. Mol Pharmacol. 2009;76:998-1010 pubmed publisher
    ..In conclusion, our data suggest that calpains and Bid act in a cooperative, but mutually independent, manner to mediate oxaliplatin-induced apoptosis of HeLa cells. ..
  43. Jost P, Grabow S, Gray D, McKenzie M, Nachbur U, Huang D, et al. XIAP discriminates between type I and type II FAS-induced apoptosis. Nature. 2009;460:1035-9 pubmed publisher
    ..These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions. ..
  44. Martinez Caballero S, Dejean L, Kinnally M, Oh K, Mannella C, Kinnally K. Assembly of the mitochondrial apoptosis-induced channel, MAC. J Biol Chem. 2009;284:12235-45 pubmed publisher
    ..5-6 nm. The mitochondrial permeability data are inconsistent with formation of lipidic pores capable of transporting megadalton-sized macromolecules as observed with recombinant Bax in liposomes. ..
  45. Schafer B, Quispe J, Choudhary V, Chipuk J, Ajero T, Du H, et al. Mitochondrial outer membrane proteins assist Bid in Bax-mediated lipidic pore formation. Mol Biol Cell. 2009;20:2276-85 pubmed publisher
    ..In sum, we propose that activated Bax induces lipidic pore formation and that MOM proteins assist cleaved Bid in this process in the absence of cardiolipin. ..
  46. Landeta O, Landajuela A, Gil D, Taneva S, Di Primo C, Sot B, et al. Reconstitution of proapoptotic BAK function in liposomes reveals a dual role for mitochondrial lipids in the BAK-driven membrane permeabilization process. J Biol Chem. 2011;286:8213-30 pubmed publisher
  47. Ren D, Tu H, Kim H, Wang G, Bean G, Takeuchi O, et al. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science. 2010;330:1390-3 pubmed publisher
    ..Thus, many forms of apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins. ..
  48. Brustovetsky T, Li T, Yang Y, Zhang J, Antonsson B, Brustovetsky N. BAX insertion, oligomerization, and outer membrane permeabilization in brain mitochondria: role of permeability transition and SH-redox regulation. Biochim Biophys Acta. 2010;1797:1795-806 pubmed publisher
  49. Petit P, Dupaigne P, Pariselli F, Gonzalvez F, Etienne F, Rameau C, et al. Interaction of the alpha-helical H6 peptide from the pro-apoptotic protein tBid with cardiolipin. FEBS J. 2009;276:6338-54 pubmed publisher
    ..These results suggest that cardiolipins at the contact sites between the two mitochondrial membranes could mediate the binding of tBid via alphaH6. ..
  50. Kushnareva Y, Andreyev A, Kuwana T, Newmeyer D. Bax activation initiates the assembly of a multimeric catalyst that facilitates Bax pore formation in mitochondrial outer membranes. PLoS Biol. 2012;10:e1001394 pubmed publisher
    ..Moreover, ATP and GTP were dispensable for MOMP. Thus, the data argue that oligomerization of a catalyst protein, distinct from Bax and Drp1, facilitates MOMP, possibly through a membrane-remodeling event. ..
  51. Weber S, Schewe J, Lehmann L, Muller S, Book M, Klaschik S, et al. Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis. Crit Care. 2008;12:R128 pubmed publisher
    ..This constellation may affect cellular susceptibility to apoptosis and complex immune dysfunction in sepsis. ..
  52. Landshamer S, Hoehn M, Barth N, Duvezin Caubet S, Schwake G, Tobaben S, et al. Bid-induced release of AIF from mitochondria causes immediate neuronal cell death. Cell Death Differ. 2008;15:1553-63 pubmed publisher
    ..In conclusion, Bid-mediated mitochondrial release of AIF followed by rapid nuclear translocation is a major mechanism of glutamate-induced neuronal death. ..
  53. Song G, Chen G, Chau D, Miao J, Lai P. Bid exhibits S phase checkpoint activation and plays a pro-apoptotic role in response to etoposide-induced DNA damage in hepatocellular carcinoma cells. Apoptosis. 2008;13:693-701 pubmed publisher
    ..The elucidation of these intricate mechanisms of Bid points to the development of a possible therapeutic option that combines cytotoxic therapies to treat HCC. ..