Skip to main content
SpringerLink
Log in

Permeabilization of the Outer Mitochondrial Membrane by Bcl-2 Proteins

  • Chapter
Proteins Membrane Binding and Pore Formation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 677))

Abstract

The proteins of the Bcl-2 family regulate the release of the apoptotic factors from mitochondria during apoptosis, a key event in physiological cell death. Although their molecular mechanisms remain unclear, the Bcl-2 proteins have been proposed to directly control the permeability of the outer mitochondrial membrane by pore formation. Indeed, they share structural features with the pore forming domains of some bacterial toxins and they can give rise to proteolipidic pores in model membranes. The complex level of regulation needed to decide the fate of the cell is achieved by an intricate interaction network between different members of the family. Current models consider multiple parallel equilibria of activation and inhibition that determine whether the permeabilization of the mitochondrial outer membrane is induced or not.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Danial NN. BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res 2007; 13:7254–7263.

    Article  CAS  PubMed  Google Scholar 

  2. Chipuk JE, Bouchier-Hayes L, Green DR. Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 2006; 13:1396–1402.

    Article  CAS  PubMed  Google Scholar 

  3. Tsujimoto Y, Cossman J, Jaffe E et al. Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985; 228:1440–1443.

    Article  CAS  PubMed  Google Scholar 

  4. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize preB-cells. Nature 1988; 335:440–442.

    Article  CAS  PubMed  Google Scholar 

  5. Wei MC, Zong WX, Cheng EH et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001; 292:727–730.

    Article  CAS  PubMed  Google Scholar 

  6. Li P, Nijhawan D, Budihardjo I et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91:479–489.

    Article  CAS  PubMed  Google Scholar 

  7. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9:47–59.

    Article  CAS  PubMed  Google Scholar 

  8. Johnson JE, Cornell RB. Amphitropic proteins: regulation by reversible membrane interactions (review). Mol Membr Biol 1999; 16:217–235.

    Article  CAS  PubMed  Google Scholar 

  9. Hockenbery D, Nuñez G, Milliman C et al. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990; 348:334–336.

    Article  CAS  PubMed  Google Scholar 

  10. Gross A, Yin XM, Wang K et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 1999; 274:1156–1163.

    Article  CAS  PubMed  Google Scholar 

  11. Hsu YT, Wolter KG, Youle RJ. Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc Natl Acad Sci USA 1997; 94:3668–3672.

    Article  CAS  PubMed  Google Scholar 

  12. Wolter KG, Hsu YT, Smith CL et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 1997; 139:1281–1292.

    Article  CAS  PubMed  Google Scholar 

  13. Zha J, Weiler S, Oh KJ et al. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 2000; 290:1761–1765.

    Article  CAS  PubMed  Google Scholar 

  14. Chou JJ, Li H, Salvesen GS et al. Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell 1999; 96:615–624.

    Article  CAS  PubMed  Google Scholar 

  15. McDonnell JM, Fushman D, Milliman CL et al. Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. Cell 1999; 96:625–634.

    Article  CAS  PubMed  Google Scholar 

  16. Muchmore SW, Sattler M, Liang H et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 1996; 381:335–341.

    Article  CAS  PubMed  Google Scholar 

  17. Suzuki M, Youle RJ, Tjandra N. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 2000; 103:645–654.

    Article  CAS  PubMed  Google Scholar 

  18. Day CL, Chen L, Richardson SJ et al. Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands. J Biol Chem 2005; 280:4738–4744.

    Article  CAS  PubMed  Google Scholar 

  19. Denisov AY, Madiraju MSR, Chen G et al. Solution structure of human BCL-w: modulation of ligand binding by the C-terminal helix. J Biol Chem 2003; 278:21124–21128.

    Article  CAS  PubMed  Google Scholar 

  20. Hinds MG, Lackmann M, Skea GL et al. The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity. EMBO J 2003; 22:1497–1507.

    Article  CAS  PubMed  Google Scholar 

  21. Moldoveanu T, Liu Q, Tocilj A et al. The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell 2006; 24:677–688.

    Article  CAS  PubMed  Google Scholar 

  22. Petros AM, Medek A, Nettesheim DG et al. Solution structure of the antiapoptotic protein bcl-2. Proceedings of the National Academy of Sciences of the United States of America 2001; 98:3012–3017.

    Article  CAS  PubMed  Google Scholar 

  23. Petros AM, Olejniczak ET, Fesik SW. Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 2004; 1644:83–94.

    CAS  PubMed  Google Scholar 

  24. Lama D, Sankararamakrishnan R. Anti-apoptotic Bcl-XL protein in complex with BH3 peptides of pro-apoptotic Bak, Bad and Bim proteins: comparative molecular dynamics simulations. Proteins 2008; 73:492–514.

    Article  CAS  PubMed  Google Scholar 

  25. Petros AM, Nettesheim DG, Wang Y et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis and biophysical studies. Protein Sci 2000; 9:2528–2534.

    CAS  PubMed  Google Scholar 

  26. Sattler M, Liang H, Nettesheim D et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 1997; 275:983–986.

    Article  CAS  PubMed  Google Scholar 

  27. Herman MD, Nyman T, Welin M et al. Completing the family portrait of the anti-apoptotic Bcl-2 proteins: crystal structure of human Bfl-1 in complex with Bim. FEBS Lett 2008; 582:3590–3594.

    Article  CAS  PubMed  Google Scholar 

  28. Gavathiotis E, Suzuki M, Davis ML et al. BAX activation is initiated at a novel interaction site. Nature 2008; 455:1076–1081.

    Article  CAS  PubMed  Google Scholar 

  29. Hinds MG, Smits C, Fredericks-Short R et al. Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death Differ 2007; 14:128–136.

    Article  CAS  PubMed  Google Scholar 

  30. Lazebnik Y. Why do regulators of apoptosis look like bacterial toxins? Curr Biol 2001; 11:R767–R768.

    Article  CAS  PubMed  Google Scholar 

  31. Desagher S, Osen-Sand A, Nichols A et al. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 1999; 144:891–901.

    Article  CAS  PubMed  Google Scholar 

  32. Hsu YT, Youle RJ. Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J Biol Chem 1998; 273:10777–10783.

    Article  CAS  PubMed  Google Scholar 

  33. Peyerl FW, Dai S, Murphy GA et al. Elucidation of some Bax conformational changes through crystallization of an antibody-peptide complex. Cell Death Differ 2007; 14:447–452.

    Article  CAS  PubMed  Google Scholar 

  34. Nechushtan A, Smith CL, Hsu YT et al. Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J 1999; 18:2330–2341.

    Article  CAS  PubMed  Google Scholar 

  35. Garcia-Saez AJ, Mingarro I, Perez-Paya E et al. Membrane-insertion fragments of Bcl-xL, Bax and Bid. Biochemistry 2004; 43:10930–10943.

    Article  CAS  PubMed  Google Scholar 

  36. Annis MG, Soucie EL, Dlugosz PJ et al. Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J 2005; 24:2096–2103.

    Article  CAS  PubMed  Google Scholar 

  37. Cartron PF, Moreau C, Oliver L et al. Involvement of the N-terminus of Bax in its intracellular localization and function. FEBS Lett 2002; 512:95–100.

    Article  CAS  PubMed  Google Scholar 

  38. Nguyen M, Millar DG, Yong VW et al. Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J Biol Chem 1993; 268:25265–25268.

    CAS  PubMed  Google Scholar 

  39. Priault M, Camougrand N, Chaudhuri B et al. Role of the C-terminal domain of Bax and Bcl-XL in their localization and function in yeast cells. FEBS Lett 1999; 443:225–228.

    Article  CAS  PubMed  Google Scholar 

  40. Ausili A, Torrecillas A, Martinez-Senac MM et al. The interaction of the Bax C-terminal domain with negatively charged lipids modifies the secondary structure and changes its way of insertion into membranes. J Struct Biol 2008; 164:146–152.

    Article  CAS  PubMed  Google Scholar 

  41. Mar Martínez-Senac M, Corbalán-García S, Gómez-Fernández JC. Conformation of the C-terminal domain of the pro-apoptotic protein Bax and mutants and its interaction with membranes. Biochemistry 2001; 40:9983–9992.

    Article  PubMed  CAS  Google Scholar 

  42. Torrecillas A, Martinez-Senac MM, Ausili A et al. Interaction of the C-terminal domain of Bcl-2 family proteins with model membranes. Biochim Biophys Acta 2007; 1768:2931–2939.

    Article  CAS  PubMed  Google Scholar 

  43. Sani MA, Dufourc EJ, Gröbner G. How does the Bax-alpha1 targeting sequence interact with mitochondrial membranes? The role of cardiolipin. Biochim Biophys Acta 2009; 1788:623–631.

    Article  CAS  PubMed  Google Scholar 

  44. Qian S, Wang W, Yang L et al. Structure of transmembrane pore induced by Bax-derived peptide: evidence for lipidic pores. Proc Natl Acad Sci USA 2008; 105:17379–17383.

    Article  CAS  PubMed  Google Scholar 

  45. Garcia-Saez AJ, Coraiola M, Dalla SM et al. Peptides derived from apoptotic Bax and Bid reproduce the poration activity of the parent full-length proteins. Biophys J 2005; 88:3976–3990.

    Article  CAS  PubMed  Google Scholar 

  46. Eskes R, Desagher S, Antonsson B et al. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 2000; 20:929–935.

    Article  CAS  PubMed  Google Scholar 

  47. Korsmeyer SJ, Wei MC, Saito M et al. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000; 7:1166–1173.

    Article  CAS  PubMed  Google Scholar 

  48. Ruffolo SC, Breckenridge DG, Nguyen M et al. BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell Death Differ 2000; 7:1101–1108.

    Article  CAS  PubMed  Google Scholar 

  49. Wei MC, Lindsten T, Mootha VK et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14:2060–2071.

    CAS  PubMed  Google Scholar 

  50. Antonsson B, Montessuit S, Lauper S et al. Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J 2000; 345:271–278.

    Article  CAS  PubMed  Google Scholar 

  51. Pagliari LJ, Kuwana T, Bonzon C et al. The multidomain proapoptotic molecules Bax and Bak are directly activated by heat. Proc Natl Acad Sci USA 2005; 102:17975–17980.

    Article  CAS  PubMed  Google Scholar 

  52. Tan C, Dlugosz PJ, Peng J et al. Auto-activation of the apoptosis protein Bax increases mitochondrial membrane permeability and is inhibited by Bcl-2. J Biol Chem 2006; 281:14764–14775.

    Article  CAS  PubMed  Google Scholar 

  53. Antonsson B, Montessuit S, Sanchez B et al. Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J Biol Chem 2001; 276:11615–11623.

    Article  CAS  PubMed  Google Scholar 

  54. Billen LP, Kokoski CL, Lovell JF et al. Bcl-XL inhibits membrane permeabilization by competing with Bax. PLoS Biol 2008; 6(6):e147.

    Article  PubMed  CAS  Google Scholar 

  55. Gross A, Jockel J, Wei MC et al. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J 1998; 17:3878–3885.

    Article  CAS  PubMed  Google Scholar 

  56. Hardwick JM, Polster BM. Bax, along with lipid conspirators, allows cytochrome c to escape mitochondria. Mol Cell 2002; 10:963–965.

    Article  CAS  PubMed  Google Scholar 

  57. Lovell JF, Billen LP, Bindner S et al. Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 2008; 135:1074–1084.

    Article  CAS  PubMed  Google Scholar 

  58. Mikhailov V, Mikhailova M, Pulkrabek DJ et al. Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane. J Biol Chem 2001; 276:18361–18374.

    Article  CAS  PubMed  Google Scholar 

  59. Roucou X, Montessuit S, Antonsson B et al. Bax oligomerization in mitochondrial membranes requires tBid (caspase-8-cleaved Bid) and a mitochondrial protein. Biochem J 2002; 368:915–921.

    Article  CAS  PubMed  Google Scholar 

  60. Saito M, Korsmeyer SJ, Schlesinger PH. BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2000; 2:553–555.

    Article  CAS  PubMed  Google Scholar 

  61. Valentijn AJ, Upton JP, Gilmore AP. Analysis of endogenous Bax complexes during apoptosis using blue native PAGE: implications for Bax activation and oligomerization. Biochem J 2008; 412:347–357.

    Article  CAS  PubMed  Google Scholar 

  62. Kuwana T, Mackey MR, Perkins G et al. Bid, Bax and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 2002; 111:331–342.

    Article  CAS  PubMed  Google Scholar 

  63. Lucken-Ardjomande S, Montessuit S, Martinou JC. Contributions to Bax insertion and oligomerization of lipids of the mitochondrial outer membrane. Cell Death Differ 2008; 15:929–937.

    Article  CAS  PubMed  Google Scholar 

  64. Lucken-Ardjomande S, Montessuit S, Martinou JC. Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes. Cell Death Differ 2008; 15:484–493.

    Article  CAS  PubMed  Google Scholar 

  65. Christenson E, Merlin S, Saito M et al. Cholesterol effects on BAX pore activation. J Mol Biol 2008; 381:1168–11683.

    Article  CAS  PubMed  Google Scholar 

  66. Giddings KS, Johnson AE, Tweten RK. Redefining cholesterol’s role in the mechanism of the cholesterol-dependent cytolysins. Proc Natl Acad Sci USA 2003; 100:11315–11320.

    Article  CAS  PubMed  Google Scholar 

  67. Dlugosz PJ, Billen LP, Annis MG et al. Bcl-2 changes conformation to inhibit Bax oligomerization. EMBO J 2006; 25:2287–2296.

    Article  CAS  PubMed  Google Scholar 

  68. Kim PK, Annis MG, Dlugosz PJ et al. During apoptosis bcl-2 changes membrane topology at both the endoplasmic reticulum and mitochondria. Mol Cell 2004; 14:523–529.

    Article  CAS  PubMed  Google Scholar 

  69. Thuduppathy GR, Hill RB. Acid destabilization of the solution conformation of Bcl-xL does not drive its pH-dependent insertion into membranes. Protein Sci 2006; 15:248–257.

    Article  CAS  PubMed  Google Scholar 

  70. Thuduppathy GR, Craig JW, Kholodenko V et al. Evidence that membrane insertion of the cytosolic domain of Bcl-xL is governed by an electrostatic mechanism. J Mol Biol 2006; 359:1045–1058.

    Article  CAS  PubMed  Google Scholar 

  71. Losonczi JA, Olejniczak ET, Betz SF et al. NMR studies of the anti-apoptotic protein Bcl-xL in micelles. Biochemistry 2000; 39:11024–11033.

    Article  CAS  PubMed  Google Scholar 

  72. Jeong SY, Gaume B, Lee YJ et al. Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers. EMBO J 2004; 23:2146–2155.

    Article  CAS  PubMed  Google Scholar 

  73. O’Neill JW, Manion MK, Maguire B et al. BCL-XL dimerization by three-dimensional domain swapping. J Mol Biol 2006; 356:367–381.

    Article  PubMed  CAS  Google Scholar 

  74. Denisov AY, Sprules T, Fraser J et al. Heat-induced dimerization of BCL-xL through alpha-helix swapping. Biochemistry 2007; 46:734–740.

    Article  CAS  PubMed  Google Scholar 

  75. Feng Y, Lin Z, Shen X et al. Bcl-xL forms two distinct homodimers at non-ionic detergents: implications in the dimerization of Bcl-2 family proteins. J Biochem 2008; 143:243–252.

    Article  CAS  PubMed  Google Scholar 

  76. Zhang Z, Lapolla SM, Annis MG et al. Bcl-2 homodimerization involves two distinct binding surfaces, a topographic arrangement that provides an effective mechanism for Bcl-2 to capture activated Bax. J Biol Chem 2004; 279:43920–43928.

    Article  CAS  PubMed  Google Scholar 

  77. Choi SY, Gonzalvez F, Jenkins GM et al. Cardiolipin deficiency releases cytochrome c from the inner mitochondrial membrane and accelerates stimuli-elicited apoptosis. Cell Death Differ 2007; 14:597–606.

    Article  CAS  PubMed  Google Scholar 

  78. Esposti MD, Cristea IM, Gaskell SJ et al. Proapoptotic Bid binds to monolysocardiolipin, a new molecular connection between mitochondrial membranes and cell death. Cell Death Differ 2003; 10:1300–1309.

    Article  CAS  PubMed  Google Scholar 

  79. Gonzalvez F, Pariselli F, Dupaigne P et al. tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak. Cell Death Differ 2005; 12:614–626.

    Article  CAS  PubMed  Google Scholar 

  80. Gonzalvez F, Bessoule JJ, Rocchiccioli F et al. Role of cardiolipin on tBid and tBid/Bax synergistic effects on yeast mitochondria. Cell Death Differ 2005; 12:659–667.

    Article  CAS  PubMed  Google Scholar 

  81. Lutter M, Fang M, Luo X et al. Cardiolipin provides specificity for targeting of tBid to mitochondria. Nat Cell Biol 2000; 2:754–761.

    Article  CAS  PubMed  Google Scholar 

  82. Gong XM, Choi J, Franzin CM et al. Conformation of membrane-associated proapoptotic tBid. J Biol Chem 2004; 279:28954–28960.

    Article  CAS  PubMed  Google Scholar 

  83. Oh KJ, Barbuto S, Meyer N et al. Conformational changes in BID, a pro-apoptotic BCL-2 family member, upon membrane binding. A site-directed spin labeling study. J Biol Chem 2005; 280:753–767.

    Article  CAS  PubMed  Google Scholar 

  84. Schendel SL, Montal M, Reed JC. Bcl-2 family proteins as ion-channels. Cell Death Differ 1998; 5:372–380.

    Article  CAS  PubMed  Google Scholar 

  85. Schlesinger PH, Gross A, Yin XM et al. Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2. Proc Natl Acad Sci USA 1997; 94:11357–11362.

    Article  CAS  PubMed  Google Scholar 

  86. Basanez G, Nechushtan A, Drozhinin O et al. Bax, but not Bcl-x(L), decreases the lifetime of planar phospholipid bilayer membranes at subnanomolar concentrations. Proc Natl Acad Sci USA 1999; 96:5492–5497.

    Article  CAS  PubMed  Google Scholar 

  87. Basanez G, Sharpe JC, Galanis J et al. Bax-type apoptotic proteins porate pure lipid bilayers through a mechanism sensitive to intrinsic monolayer curvature. J Biol Chem 2002; 277:49360–49365.

    Article  CAS  PubMed  Google Scholar 

  88. Epand RF, Martinou JC, Montessuit S et al. Transbilayer lipid diffusion promoted by Bax: implications for apoptosis. Biochemistry 2003; 42:14576–14582.

    Article  CAS  PubMed  Google Scholar 

  89. Garcia-Saez AJ, Coraiola M, Serra MD et al. Peptides corresponding to helices 5 and 6 of Bax can independently form large lipid pores. Febs Journal 2006; 273:971–981.

    Article  CAS  PubMed  Google Scholar 

  90. Terrones O, Antonsson B, Yamaguchi H et al. Lipidic pore formation by the concerted action of proapoptotic BAX and tBID. Journal of Biological Chemistry 2004; 279:30081–30091.

    Article  CAS  PubMed  Google Scholar 

  91. Schafer B, Quispe J, Choudhary V et al. Mitochondrial outer membrane proteins assist Bid in Bax-mediated lipidic pore formation. Molecular Biology of the Cell 2009; 20:2276–2285.

    Article  CAS  PubMed  Google Scholar 

  92. Jürgensmeier JM, Xie Z, Deveraux Q et al. Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 1998; 95:4997–5002.

    Article  PubMed  Google Scholar 

  93. Zha H, Fisk HA, Yaffe MP et al. Structure-function comparisons of the proapoptotic protein Bax in yeast and mammalian cells. Mol Cell Biol 1996; 16:6494–6508.

    CAS  PubMed  Google Scholar 

  94. Heimlich G, McKinnon AD, Bernardo K et al. Bax-induced cytochrome c release from mitochondria depends on alpha-helices-5 and-6. Biochem J 2004; 378:247–255.

    Article  CAS  PubMed  Google Scholar 

  95. Asoh S, Ohtsu T, Ohta S. The super anti-apoptotic factor Bcl-xFNK constructed by disturbing intramolecular polar interactions in rat Bcl-xL. J Biol Chem 2000; 275:37240–37245.

    Article  CAS  PubMed  Google Scholar 

  96. Matsuyama S, Schendel SL, Xie Z et al. Cytoprotection by Bcl-2 requires the pore-forming alpha5 and alpha6 helices. J Biol Chem 1998; 273:30995–31001.

    Article  CAS  PubMed  Google Scholar 

  97. Nouraini S, Six E, Matsuyama S et al. The putative pore-forming domain of Bax regulates mitochondrial localization and interaction with Bcl-X(L). Mol Cell Biol 2000; 20:1604–1615.

    Article  CAS  PubMed  Google Scholar 

  98. Epand RF, Martinou JC, Montessuit S et al. Direct evidence for membrane pore formation by the apoptotic protein Bax. Biochem Biophys Res Commun 2002; 298:744–749.

    Article  CAS  PubMed  Google Scholar 

  99. Sobko AA, Kotova EA, Antonenko YN et al. Effect of lipids with different spontaneous curvature on the channel activity of colicin E1: evidence in favor of a toroidal pore. FEBS Lett 2004; 576:205–210.

    Article  CAS  PubMed  Google Scholar 

  100. Sobko AA, Kotova EA, Antonenko YN et al. Lipid dependence of the channel properties of a colicin E1-lipid toroidal pore. J Biol Chem 2006; 281:14408–1446.

    Article  CAS  PubMed  Google Scholar 

  101. Lee MT, Hung WC, Chen FY et al. Mechanism and kinetics of pore formation in membranes by water-soluble amphipathic peptides. Proc Natl Acad Sci USA 2008; 105:5087–5092.

    Article  CAS  PubMed  Google Scholar 

  102. Huang HW. Free energies of molecular bound States in lipid bilayers: lethal concentrations of antimicrobial peptides. Biophys J 2009; 96:3263–3272.

    Article  CAS  PubMed  Google Scholar 

  103. Garcia-Saez AJ, Chiantia S, Salgado J et al. Pore formation by a Bax-derived peptide: Effect on the line tension of the membrane probed by AFM. Biophys J 2007; 93:103–112.

    Article  CAS  PubMed  Google Scholar 

  104. Minn AJ, Velez P, Schendel SL et al. Bcl-x(L) forms an ion channel in synthetic lipid membranes. Nature 1997; 385:353–357.

    Article  CAS  PubMed  Google Scholar 

  105. Thuduppathy GR, Terrones O, Craig JW et al. The N-terminal domain of Bcl-xL reversibly binds membranes in a pH-dependent manner. Biochemistry 2006; 45:14533–14542.

    Article  CAS  PubMed  Google Scholar 

  106. Peng J, Tan C, Roberts GJ et al. tBid elicits a conformational alteration in membrane-bound Bcl-2 such that it inhibits Bax pore formation. J Biol Chem 2006; 281:35802–35811.

    Article  CAS  PubMed  Google Scholar 

  107. Peng J, Lapolla SM, Zhang Z et al. The cytosolic domain of Bcl-2 forms small pores in model mitochondrial outer membrane after acidic pH-induced membrane association. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2009; 26:130–137.

    CAS  PubMed  Google Scholar 

  108. Basanez G, Zhang J, Chau BN et al. Pro-apoptotic cleavage products of Bcl-x(L) form cytochrome c-conducting pores in pure lipid membranes. J Biol Chem 2001; 276:31083–31091.

    Article  CAS  PubMed  Google Scholar 

  109. Cheng EH, Kirsch DG, Clem RJ et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 1997; 278:1966–1968.

    Article  CAS  PubMed  Google Scholar 

  110. Jonas EA, Hickman JA, Chachar M et al. Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals. Proc Natl Acad Sci USA 2004; 101:13590–13595.

    Article  CAS  PubMed  Google Scholar 

  111. Lin B, Kolluri SK, Lin F et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 2004; 116:527–540.

    Article  CAS  PubMed  Google Scholar 

  112. Wei MC, Lindsten T, Mootha VK et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14:2060–2071.

    CAS  PubMed  Google Scholar 

  113. Zong WX, Lindsten T, Ross AJ et al. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001; 15:1481–1486.

    Article  CAS  PubMed  Google Scholar 

  114. Epand RF, Martinou JC, Fornallaz-Mulhauser M et al. The apoptotic protein tBid promotes leakage by altering membrane curvature. J Biol Chem 2002; 277:32632–32639.

    Article  CAS  PubMed  Google Scholar 

  115. Kudla G, Montessuit S, Eskes R et al. The destabilization of lipid membranes induced by the C-terminal fragment of caspase 8-cleaved bid is inhibited by the N-terminal fragment. J Biol Chem 2000; 275:22713–22718.

    Article  CAS  PubMed  Google Scholar 

  116. Schendel SL, Azimov R, Pawlowski K et al. Ion channel activity of the BH3 only Bcl-2 family member, BID. J Biol Chem 1999; 274:21932–21936.

    Article  CAS  PubMed  Google Scholar 

  117. Yan L, Miao Q, Sun Y et al. tBid forms a pore in the liposome membrane. FEBS Lett 2003; 555:545–550.

    Article  CAS  PubMed  Google Scholar 

  118. Epand RF, Martinou JC, Fornallaz-Mulhauser M et al. The apoptotic protein tBid promotes leakage by altering membrane curvature. J Biol Chem 2002; 277:32632–32639.

    Article  CAS  PubMed  Google Scholar 

  119. Esposti MD, Erler JT, Hickman JA et al. Bid, a widely expressed proapoptotic protein of the Bcl-2 family, displays lipid transfer activity. Mol Cell Biol 2001; 21:7268–7276.

    Article  CAS  PubMed  Google Scholar 

  120. Esposti MD. The roles of Bid. Apoptosis 2002; 7:433–440.

    Article  CAS  PubMed  Google Scholar 

  121. Grad JM, Zeng XR, Boise LH. Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Curr Opin Oncol 2000; 12:543–549.

    Article  CAS  PubMed  Google Scholar 

  122. Gardai SJ, Hildeman DA, Frankel SK et al. Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 2004; 279:21085–21095.

    Article  CAS  PubMed  Google Scholar 

  123. Kim BJ, Ryu SW, Song BJ. JNK-and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 2006; 281:21256–21265.

    Article  CAS  PubMed  Google Scholar 

  124. Linseman DA, Butts BD, Precht TA et al. Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 2004; 24:9993–10002.

    Article  CAS  PubMed  Google Scholar 

  125. Zhong Q, Gao W, Du F et al. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 2005; 121:1085–1095.

    Article  CAS  PubMed  Google Scholar 

  126. Akiyama T, Bouillet P, Miyazaki T et al. Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. EMBO J 2003; 22:6653–6664.

    Article  CAS  PubMed  Google Scholar 

  127. Tran SE, Meinander A, Eriksson JE. Instant decisions: transcription-independent control of death-receptor-mediated apoptosis. Trends Biochem Sci 2004; 29:601–608.

    Article  CAS  PubMed  Google Scholar 

  128. Oda E, Ohki R, Murasawa H et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288:1053–1058.

    Article  CAS  PubMed  Google Scholar 

  129. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001; 7:683–694.

    Article  CAS  PubMed  Google Scholar 

  130. Dijkers PF, Medema RH, Lammers JW et al. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 2000; 10:1201–1204.

    Article  CAS  PubMed  Google Scholar 

  131. Li H, Zhu H, Xu CJ et al. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94:491–501.

    Article  CAS  PubMed  Google Scholar 

  132. . Zha J, Harada H, Yang E et al. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 1996; 87:619–628.

    Article  CAS  PubMed  Google Scholar 

  133. Ley R, Ewings KE, Hadfield K et al. Regulatory phosphorylation of Bim: sorting out the ERK from the JNK. Cell Death Differ 2005; 12:1008–10014.

    Article  CAS  PubMed  Google Scholar 

  134. Puthalakath H, Huang DC, O’Reilly LA et al. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 1999; 3:287–296.

    Article  CAS  PubMed  Google Scholar 

  135. Puthalakath H, Villunger A, O’Reilly LA et al. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 2001; 293:1829–1832.

    Article  CAS  PubMed  Google Scholar 

  136. Goping IS, Gross A, Lavoie JN et al. Regulated targeting of BAX to mitochondria. J Cell Biol 1998; 143:207–215.

    Article  CAS  PubMed  Google Scholar 

  137. Yethon JA, Epand RF, Leber B et al. Interaction with a membrane surface triggers a reversible conformational change in Bax normally associated with induction of apoptosis. J Biol Chem 2003; 278:48935–48941.

    Article  CAS  PubMed  Google Scholar 

  138. Mikhailov V, Mikhailova M, Degenhardt K et al. Association of Bax and Bak homo-oligomers in mitochondria. Bax requirement for Bak reorganization and cytochrome c release. J Biol Chem 2003; 278:5367–5376.

    Article  CAS  PubMed  Google Scholar 

  139. Willis SN, Fletcher JI, Kaufmann T et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 2007; 315:856–859.

    Article  CAS  PubMed  Google Scholar 

  140. Willis SN, Chen L, Dewson G et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 2005; 19:1294–1305.

    Article  CAS  PubMed  Google Scholar 

  141. Zhou L, Chang DC. Dynamics and structure of the Bax-Bak complex responsible for releasing mitochondrial proteins during apoptosis. J Cell Sci 2008; 121:218621–96.

    Article  CAS  Google Scholar 

  142. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74:609–619.

    Article  CAS  PubMed  Google Scholar 

  143. Korsmeyer SJ, Shutter JR, Veis DJ et al. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol 1993; 4:327–332.

    CAS  PubMed  Google Scholar 

  144. Veis DJ, Sorenson CM, Shutter JR et al. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys and hypopigmented hair. Cell 1993; 75:229–240.

    Article  CAS  PubMed  Google Scholar 

  145. Motoyama N, Wang F, Roth KA et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 1995; 267:1506–1510.

    Article  CAS  PubMed  Google Scholar 

  146. Shindler KS, Latham CB, Roth KA. Bax deficiency prevents the increased cell death of immature neurons in bcl-x-deficient mice. J Neurosci 1997; 17:3112–3119.

    CAS  PubMed  Google Scholar 

  147. Chen L, Willis SN, Wei A et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005; 17:393–403.

    Article  CAS  PubMed  Google Scholar 

  148. Nijhawan D, Fang M, Traer E et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev 2003; 17:1475–1486.

    Article  CAS  PubMed  Google Scholar 

  149. Hausmann G, O’Reilly LA, van Driel R et al. Pro-apoptotic apoptosis protease-activating factor 1 (Apaf-1) has a cytoplasmic localization distinct from Bcl-2 or Bcl-x(L). J Cell Biol 2000; 149:623–634.

    Article  CAS  PubMed  Google Scholar 

  150. Wilson-Annan J, O’Reilly LA, Crawford SA et al. Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity. J Cell Biol 2003; 162:877–887.

    Article  CAS  PubMed  Google Scholar 

  151. Leber B, Lin J, Andrews DW. Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis 2007; 12:897–911.

    Article  CAS  PubMed  Google Scholar 

  152. Leu JI, Dumont P, Hafey M et al. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 2004; 6:443–450.

    Article  CAS  PubMed  Google Scholar 

  153. Kuwana T, Bouchier-Hayes L, Chipuk JE et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 2005; 17:525–535.

    Article  CAS  PubMed  Google Scholar 

  154. Terrones O, Etxebarria A, Landajuela A et al. BIM and tBID are not mechanistically equivalent when assisting BAX to permeabilize bilayer membranes. J Biol Chem 2008; 283:7790–7803.

    Article  CAS  PubMed  Google Scholar 

  155. Chipuk JE, Fisher JC, Dillon CP et al. Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins. Proc Natl Acad Sci USA 2008; 105, 20327–20332..

    Article  CAS  PubMed  Google Scholar 

  156. Jaysinghe S, Hristova K, Wimley W et al. http://blanco.biomol.uci.edu/mpex. 2008.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. BIOTEC der TU Dresden, Tatzberg 45-51, 01307, Dresden, Germany

    Ana J. García-Sáez

  2. Instituto de Ciencia Molecular, University of Valencia, Pol. La Coma, Paterna, Valencia, Spain

    Gustavo Fuertes & Jesús Salgado

  3. Medizinisch Theoretisches Zeutrum der TU Dresden, Dresden, Germany

    Jacob Suckale

Authors
  1. Ana J. García-Sáez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gustavo Fuertes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jacob Suckale
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jesús Salgado
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana J. García-Sáez .

Editor information

Editors and Affiliations

  1. Department of Biology, University of Ljubljana, Ljubljana, Slovenia

    Gregor Anderluh PhD

  2. Institute for Cell and Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK

    Jeremy Lakey PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

García-Sáez, A.J., Fuertes, G., Suckale, J., Salgado, J. (2010). Permeabilization of the Outer Mitochondrial Membrane by Bcl-2 Proteins. In: Anderluh, G., Lakey, J. (eds) Proteins Membrane Binding and Pore Formation. Advances in Experimental Medicine and Biology, vol 677. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6327-7_8

Download citation

Publish with us

Policies and ethics

Search

Navigation