Interaction with a Membrane Surface Triggers a Reversible Conformational Change in Bax Normally Associated with Induction of Apoptosis

The Bcl-2 family member Bax is an apoptosis-promoting protein that normally resides in an inactive state within the cytoplasm of healthy cells. Upon induction of apoptosis by diverse stimuli, Bax undergoes a conformational change and translocates to mitochondria, where it oligomerizes and forms pores that allow the release of cytochrome c and other cytotoxic factors. Protein-protein interactions between Bax and other Bcl-2 family members are strongly implicated in Bax activation, but a compelling case has recently been made for the involvement of lipids in this process as well. Here we report that purified Bax undergoes a reversible conformational change upon incubation with lipid vesicles in the absence of other proteins. This Bax-liposome interaction does not depend on a specific lipid composition. Changes in Bax conformation were observed by immunoprecipitation with the conformation-specific antibody 6A7, circular dichroism spectroscopy, and differential scanning calorimetry. Although liposomes induced Bax to become 6A7-reactive (a feature normally associated with the onset of apoptosis), the protein did not insert into membranes, become oligomeric, or form pores, clearly indicating that other triggers are required for Bax to achieve its final pro-apoptotic state. Indeed, the lipid-induced Bax conformational change is shown to be required for tBid-induced Bax oligomerization and pore formation, putting it upstream of tBid activity in this molecular pathway to Bax activation. These data demonstrate that Bax is sensitized to activation by transient interaction with lipid membrane surfaces and provide evidence that Bax activation proceeds in a stepwise fashion, with multiple triggers and potential levels of regulation. The Bcl-2 family member Bax is an apoptosis-promoting protein that normally resides in an inactive state within the cytoplasm of healthy cells. Upon induction of apoptosis by diverse stimuli, Bax undergoes a conformational change and translocates to mitochondria, where it oligomerizes and forms pores that allow the release of cytochrome c and other cytotoxic factors. Protein-protein interactions between Bax and other Bcl-2 family members are strongly implicated in Bax activation, but a compelling case has recently been made for the involvement of lipids in this process as well. Here we report that purified Bax undergoes a reversible conformational change upon incubation with lipid vesicles in the absence of other proteins. This Bax-liposome interaction does not depend on a specific lipid composition. Changes in Bax conformation were observed by immunoprecipitation with the conformation-specific antibody 6A7, circular dichroism spectroscopy, and differential scanning calorimetry. Although liposomes induced Bax to become 6A7-reactive (a feature normally associated with the onset of apoptosis), the protein did not insert into membranes, become oligomeric, or form pores, clearly indicating that other triggers are required for Bax to achieve its final pro-apoptotic state. Indeed, the lipid-induced Bax conformational change is shown to be required for tBid-induced Bax oligomerization and pore formation, putting it upstream of tBid activity in this molecular pathway to Bax activation. These data demonstrate that Bax is sensitized to activation by transient interaction with lipid membrane surfaces and provide evidence that Bax activation proceeds in a stepwise fashion, with multiple triggers and potential levels of regulation. Programmed cell death in multicellular organisms is regulated by the Bcl-2 family of proteins (1.Cory S. Adams J.M. Nat. Rev. Cancer. 2002; 2: 647-656Crossref PubMed Scopus (3308) Google Scholar). Some proteins within this family promote apoptosis, whereas others promote survival, but the exact molecular mechanisms by which these proteins function are still largely unknown. Bax is a pro-apoptotic member of the Bcl-2 family of cell death regulators (2.Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Cell. 1993; 74: 609-619Abstract Full Text PDF PubMed Scopus (5853) Google Scholar). In healthy cells, Bax resides in the cytoplasm (3.Hsu Y.T. Wolter K.G. Youle R.J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3668-3672Crossref PubMed Scopus (1025) Google Scholar), but upon induction of apoptosis by diverse stimuli, Bax undergoes a conformational change involving both its N and C termini (4.Goping I.S. Gross A. Lavoie J.N. Nguyen M. Jemmerson R. Roth K. Korsmeyer S.J. Shore G.C. J. Cell Biol. 1998; 143: 207-215Crossref PubMed Scopus (548) Google Scholar, 5.Sundararajan R. White E. J. Virol. 2001; 75: 7506-7516Crossref PubMed Scopus (79) Google Scholar) and translocates to and inserts into membranes of the mitochondria and endoplasmic reticulum (ER) 1The abbreviations used are: ERendoplasmic reticulumPCphosphatidylcholinePEphosphatidylethanolaminePIphosphatidylinositolPSphosphatidylserineDOdioleoylANTS8-aminonaphthalene 1,3,6-trisulfonic acidDPXp-xylene-bis-pyridinium bromideCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonateCBDchitin-binding domainCDcircular dichroismDSCdifferential scanning calorimetryOGoctyl glucoside.1The abbreviations used are: ERendoplasmic reticulumPCphosphatidylcholinePEphosphatidylethanolaminePIphosphatidylinositolPSphosphatidylserineDOdioleoylANTS8-aminonaphthalene 1,3,6-trisulfonic acidDPXp-xylene-bis-pyridinium bromideCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonateCBDchitin-binding domainCDcircular dichroismDSCdifferential scanning calorimetryOGoctyl glucoside. (6.Wolter K.G. Hsu Y.T. Smith C.L. Nechushtan A. Xi X.G. Youle R.J. J. Cell Biol. 1997; 139: 1281-1292Crossref PubMed Scopus (1569) Google Scholar, 7.Nechushtan A. Smith C.L. Lamensdorf I. Yoon S.H. Youle R.J. J. Cell Biol. 2001; 153: 1265-1276Crossref PubMed Scopus (403) Google Scholar). In the mitochondrial outer membrane, Bax becomes homo-oligomeric (8.Antonsson B. Montessuit S. Sanchez B. Martinou J.C. J. Biol. Chem. 2001; 276: 11615-11623Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar) and forms pores (9.Epand R.F. Martinou J.C. Montessuit S. Epand R.M. Yip C.M. Biochem. Biophys. Res. Commun. 2002; 298: 744-749Crossref PubMed Scopus (94) Google Scholar) that allow the release of cytochrome c and other pro-apoptotic factors. Bax at the ER is implicated in the regulation of calcium ion fluxes (10.Nutt L.K. Chandra J. Pataer A. Fang B. Roth J.A. Swisher S.G. O'Neil R.G. McConkey D.J. J. Biol. Chem. 2002; 277: 20301-20308Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 11.Scorrano L. Oakes S.A. Opferman J.T. Cheng E.H. Sorcinelli M.D. Pozzan T. Korsmeyer S.J. Science. 2003; 300: 135-139Crossref PubMed Scopus (1222) Google Scholar), which can lead to opening of the permeability transition pore in mitochondria, again resulting in cytochrome c release and caspase activation. endoplasmic reticulum phosphatidylcholine phosphatidylethanolamine phosphatidylinositol phosphatidylserine dioleoyl 8-aminonaphthalene 1,3,6-trisulfonic acid p-xylene-bis-pyridinium bromide 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate chitin-binding domain circular dichroism differential scanning calorimetry octyl glucoside. endoplasmic reticulum phosphatidylcholine phosphatidylethanolamine phosphatidylinositol phosphatidylserine dioleoyl 8-aminonaphthalene 1,3,6-trisulfonic acid p-xylene-bis-pyridinium bromide 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate chitin-binding domain circular dichroism differential scanning calorimetry octyl glucoside. Regulation of Bax activity is thus a critical determinant of cell fate. Protein-protein interactions between Bax and other Bcl-2 family members are key to this regulation. For example, Bid is a pro-apoptotic member of the Bcl-2 protein family that is processed by proteolytic cleavage to an activated form (tBid) in response to death receptor signaling (12.Li H. Zhu H. Xu C.J. Yuan J. Cell. 1998; 94: 491-501Abstract Full Text Full Text PDF PubMed Scopus (3774) Google Scholar), and tBid subsequently functions as a potent Bax activator to induce apoptosis (13.Desagher S. Osen-Sand A. Nichols A. Eskes R. Montessuit S. Lauper S. Maundrell K. Antonsson B. Martinou J.C. J. Cell Biol. 1999; 144: 891-901Crossref PubMed Scopus (1092) Google Scholar, 14.Eskes R. Desagher S. Antonsson B. Martinou J.C. Mol. Cell. Biol. 2000; 20: 929-935Crossref PubMed Scopus (1014) Google Scholar). Conversely, Bcl-XL is an anti-apoptotic Bcl-2 family protein that has been reported to heterodimerize with Bax and nullify its activity (15.Yang E. Zha J. Jockel J. Boise L.H. Thompson C.B. Korsmeyer S.J. Cell. 1995; 80: 285-291Abstract Full Text PDF PubMed Scopus (1889) Google Scholar). Regulation of Bax activity may also depend on interactions with non-Bcl-2 family members; Ku70 (part of the regulatory subunit of DNA-dependent protein kinase) and humanin (a 24-amino acid anti-apoptotic peptide encoded in mammalian genomes) have both been shown to interact with Bax in the cytoplasm and prevent its translocation to membranes (16.Guo B. Zhai D. Cabezas E. Welsh K. Nouraini S. Satterthwait A.C. Reed J.C. Nature. 2003; 423: 456-461Crossref PubMed Scopus (465) Google Scholar, 17.Sawada M. Sun W. Hayes P. Leskov K. Boothman D.A. Matsuyama S. Nat. Cell Biol. 2003; 5: 320-329Crossref PubMed Scopus (317) Google Scholar). A compelling case has also been made that lipids play a role in Bax pore formation. For example, in the absence of other proteins, the permeabilization of liposomes induced by detergent-activated Bax has been shown to depend on both intrinsic monolayer curvature (18.Basanez G. Sharpe J.C. Galanis J. Brandt T.B. Hardwick J.M. Zimmerberg J. J. Biol. Chem. 2002; 277: 49360-49365Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar) and on the mitochondria-specific lipid cardiolipin (19.Epand R.F. Martinou J.C. Montessuit S. Epand R.M. Biochem. J. 2002; 367: 849-855Crossref PubMed Scopus (38) Google Scholar, 20.Kuwana T. Mackey M.R. Perkins G. Ellisman M.H. Latterich M. Schneiter R. Green D.R. Newmeyer D.D. Cell. 2002; 111: 331-342Abstract Full Text Full Text PDF PubMed Scopus (1218) Google Scholar). In addition, visualization of apoptotic cells by confocal microscopy shows that Bax oligomerization occurs primarily at discrete foci on mitochondria, which subsequently become sites of mitochondrial fission (21.Karbowski M. Lee Y.J. Gaume B. Jeong S.Y. Frank S. Nechushtan A. Santel A. Fuller M. Smith C.L. Youle R.J. J. Cell Biol. 2002; 159: 931-938Crossref PubMed Scopus (667) Google Scholar). Based on these and other data, it has been hypothesized that Bax may function to disrupt membranes via formation of pores, as observed membrane fission and in M.D. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google and J.M. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). pores be to allow the release of not cytochrome c the mitochondrial but also the release of other apoptotic as and Indeed, Bax is reported to be of liposomes to of to T. Mackey M.R. Perkins G. Ellisman M.H. Latterich M. Schneiter R. Green D.R. Newmeyer D.D. Cell. 2002; 111: 331-342Abstract Full Text Full Text PDF PubMed Scopus (1218) Google Scholar). in pore formation, lipids play an role in Bax this and the molecular of Bax activation, we purified Bax interact with liposomes of mitochondrial by for the in of Bax conformational membrane and and pore formation. data demonstrate that Bax undergoes a transient conformational change upon interaction with a lipid membrane indicating a role for lipids in the regulation of Bax this interaction is shown to be a for tBid-induced Bax oligomerization and pore formation, the of this conformational change to Bax activation. were and phosphatidylethanolamine were purified and cardiolipin were as lipids in dioleoyl or 1,3,6-trisulfonic acid and p-xylene-bis-pyridinium bromide were and were were ER membranes were purified P. G. PubMed Scopus Google Scholar), and mitochondria were PubMed Scopus Google Scholar). Bax and were Bax with acid in and purified as an domain as M. Youle R.J. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of E. by with a and at the protein to that the Bax with a and release of Bax its by incubation with for The protein to a of and in the with to the Bax in and and at Bax by the purified protein in octyl for at as reported B. Montessuit S. Lauper S. Eskes R. Martinou J.C. Biochem. J. 2000; PubMed Scopus Google Scholar). Bcl-XL with acid purified as an as to the as as to prevent protein and The protein the purified by interaction a of Bcl-XL the in and and at Bid with an purified and with caspase as J. S. Korsmeyer S.J. Science. 2000; PubMed Scopus Google Scholar). The of Bid (tBid) purified the Bid and caspase as J. S. Korsmeyer S.J. Science. 2000; PubMed Scopus Google Scholar). were to be on of were in the in the of the mitochondrial outer membrane, liposomes were made of and The by a of by incubation for in a to were in to and vesicles were by and were in the and and were by a of with the conformation-specific antibody were in in at Bax and liposomes were at of and of protein and of to on a In the absence of or were at as and were by with protein for by for The were with A with an with C were the in and by with the Bax the of Bax protein and liposomes were for a of a and protein liposomes a of with a The resulting an of The were and into and antibody at and by immunoprecipitation as were an were by a Bax into and The of the Bax by acid lipids were as a that in and to of The final of Bax in were for the and in of were and with the S.Y. Sci. 1999; PubMed Scopus Google Scholar). were by the of Bax at were at a or of to and to to the of the of the at as were an with the For Bax were and the final used in the and were to lipids were as a on the of a to protein of the protein to the and by and of were of were at a of and Bax used at a of with lipid vesicles and Bax were at a lipid to protein of for at in A of this to a final of of with of in and of in were at for and were the The the to the and whereas the the of the The were with of to an of protein that or to the of the of Bax a in and The to the in a of at a of and were at the and by with antibody for Bax release liposomes by the of the in a an of and the to at were by the the between and The of release is reported as a of the by of the liposomes with The for liposomes did not change the of the indicating that the for the liposomes did not change the of the indicating that not a were at and to to Bax and lipid were used at of and The tBid and Bcl-XL proteins were used at of and were a at which the a a in Bax by antibody an at the N of Bax that is in its inactive state but that becomes upon Bax activation Y.T. Youle R.J. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Bax does not with but can be induced to the conformation by incubation in the as reported Y.T. Youle R.J. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). incubation of Bax with liposomes of mitochondrial outer membrane also to This is the not in cells where mitochondrial membranes this were on of Bax for with purified mitochondria and or ER membranes and were by the of or a to mitochondria ER membranes the conformational change that observed with liposomes This is in the of Bax has recently been shown to depend upon the of the mitochondria-specific lipid cardiolipin (19.Epand R.F. Martinou J.C. Montessuit S. Epand R.M. Biochem. J. 2002; 367: 849-855Crossref PubMed Scopus (38) Google Scholar, 20.Kuwana T. Mackey M.R. Perkins G. Ellisman M.H. Latterich M. Schneiter R. Green D.R. Newmeyer D.D. Cell. 2002; 111: 331-342Abstract Full Text Full Text PDF PubMed Scopus (1218) Google Scholar), we to lipids were also critical to this were on of Bax with and of induced and indicating that the change in Bax is not cardiolipin other lipid vesicles of the were with (a that does not Bax to with the on Bax conformation the induction of Bax on an lipid which be by the of lipids in with both and liposomes the conformational change in the interaction is not by were on of Bax and liposomes in with to The not the that the lipid-induced change in Bax is not to of Bax activation a on the of R. Antonsson B. Osen-Sand A. Montessuit S. R. G. Nichols A. Martinou J.C. J. Cell Biol. 1998; 143: PubMed Scopus Google Scholar) or (19.Epand R.F. Martinou J.C. Montessuit S. Epand R.M. Biochem. J. 2002; 367: 849-855Crossref PubMed Scopus (38) Google Scholar) in and of pore formation by the G. M. M. G. J. 2003; PubMed Google Scholar). were to of these the lipid Bax conformational but or by observed not to the Bax conformational change induced by lipid a or reversible protein and liposomes were for a of and protein liposomes by a of of Bax to liposomes in these not also The Bax protein were and into and antibody at and by Bax that not been to liposomes also a were into and with or as and The are in and that the lipid-induced conformational change in Bax is Bax not be with the antibody antibody were were in which protein and liposomes were by the data not In the of the Bax is is not cardiolipin other is not by and the of an lipid of the Bax by with a of the the of Bax and These with reported by M. Youle R.J. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In the of the and The of by the of the at an transition with of between and with the of the transition at This transition is and in a of of the the that the is still in The of Bax that it is a protein with Bax is a it does not proteins, of which at In the of the transition of Bax and reversible with an of of the These data are with the process to a for a of Bax shows that the of Bax in the of lipid in of the Bax by the for Bax in the and absence of lipid vesicles are in were observed upon or The transition for Bax at by transition observed by is for by the of in is to have a on the of proteins K. 20: PubMed Scopus Google In the of lipid a transition that for Bax indicating that Bax a state as a of the molecular by the lipid The exact and of the for the in to to as the protein to lipid or the and of both the and the data demonstrate that the interaction of Bax with lipid vesicles a of Bax to a The Bax or the of on Bax were to the lipid-induced conformational change in Bax in membrane for liposomes and protein are at the of a Upon liposomes with associated Bax to the of the Bax used as a it the of the activated membrane B. Montessuit S. Lauper S. Eskes R. Martinou J.C. Biochem. J. 2000; PubMed Scopus Google Scholar). The conformational change induced by incubation with liposomes does not in Bax membrane Bax not the incubation with whereas with the octyl protein key feature of Bax activation is the formation of liposomes induce the formation of Bax both and protein were for at and to The of in the the of Bax as a that in Bax that with liposomes has the but a is in molecular to octyl Bax as the is the form into molecular as B. Montessuit S. Lauper S. Eskes R. Martinou J.C. Biochem. J. 2000; PubMed Scopus Google Scholar). incubation of Bax with liposomes does not with T. Mackey M.R. Perkins G. Ellisman M.H. Latterich M. Schneiter R. Green D.R. Newmeyer D.D. Cell. 2002; 111: 331-342Abstract Full Text Full Text PDF PubMed Scopus (1218) Google Scholar, Montessuit S. Antonsson B. Martinou J.C. Biochem. J. 2002; PubMed Scopus Google Scholar). we the that the lipid-induced conformational change in Bax pore formation. This on the data that liposomes not induce Bax membrane or we it a the conformation of Bax is associated with its of Bax and liposomes did not in release with the octyl that the lipid-induced of the Bax is of liposomes induce a conformational change in Bax that the this conformation of Bax does not membrane or pore formation. The a for tBid-induced Bax and and by the of the lipid-induced Bax conformational we to its to tBid-induced Bax activation, a molecular pathway to tBid is to induce Bax oligomerization and pore formation, we Bax and tBid and the of Bax both in the and absence of liposomes tBid to induce Bax oligomerization membrane in the of that the lipid-induced Bax conformational change upstream of tBid tBid also to induce the conformational change in Bax that is by the antibody Bax does become 6A7-reactive in the of both liposomes and tBid again that the lipid-induced of the Bax occurs as a to tBid the lipid-induced Bax conformational change thus the at which the anti-apoptotic protein Bcl-XL its were on of Bax with liposomes and Bcl-XL Bcl-XL did not it can be that Bcl-XL of the interaction to Bax activation. The proteins used in these were to be by of and to be by release for membrane permeabilization These data demonstrate that Bax tBid are to release the of the to membrane The of anti-apoptotic Bcl-XL as on its anti-apoptotic function a conformational change in Bax that in and both that this lipid-induced conformational change Bax to a and the Bax is in healthy cells and becomes upon or apoptotic Indeed, data that mitochondria and ER membranes not the in Bax as liposomes can be in of is in for this is the of in purified protein and other potential proteins have been the Bcl-2 family Ku70 and humanin (16.Guo B. Zhai D. Cabezas E. Welsh K. Nouraini S. Satterthwait A.C. Reed J.C. Nature. 2003; 423: 456-461Crossref PubMed Scopus (465) Google Scholar, 17.Sawada M. Sun W. Hayes P. Leskov K. Boothman D.A. Matsuyama S. Nat. Cell Biol. 2003; 5: 320-329Crossref PubMed Scopus (317) Google Scholar), and other other proteins interact with Bax to prevent the lipid-induced conformational or to the membrane of a does not the of For example, membranes are the for the Bax conformational change a transient interaction with the or with a of proteins have shown that it is to be an of membrane or may Bax into the membrane by the protein via the conformational change these and have observed that mitochondrial membranes that have been by induce in whereas mitochondria not H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). a potential for this the may in the membrane and allow transient interactions to with the that induce in to an has recently been made that Bax oligomerization occurs at discrete foci on mitochondria, which subsequently become sites of mitochondrial fission (21.Karbowski M. Lee Y.J. Gaume B. Jeong S.Y. Frank S. Nechushtan A. Santel A. Fuller M. Smith C.L. Youle R.J. J. Cell Biol. 2002; 159: 931-938Crossref PubMed Scopus (667) Google Scholar). these sites are clearly in the of the membrane and in the protein both of which are to the observed of Bax the and membrane at these mitochondrial sites a to is observed with in is also a in the for that the Bax is reversible upon of the case a cell and A. J.A. J. 2001; 20: PubMed Scopus Google Scholar) that conformational at the N of Bax are induced by cytotoxic or of and that these are data the L.H. J. Cell Biol. 2000; PubMed Scopus Google Scholar) also that Bax conformational the N can be in cells of the Bax that is normally becomes but upon this is again in both of these the conformational at the Bax N were not to the cells to is the of Bax a of proteins and we have shown that the lipid-induced Bax conformational change is a to tBid tBid does not Bax or tBid and Bax are in the of Bax becomes 6A7-reactive and tBid is subsequently to induce Bax oligomerization and pore formation is that the Bax conformational change an and in the Bax activation In of this Shore and (4.Goping I.S. Gross A. Lavoie J.N. Nguyen M. Jemmerson R. Roth K. Korsmeyer S.J. Shore G.C. J. Cell Biol. 1998; 143: 207-215Crossref PubMed Scopus (548) Google Scholar) have at the Bax N and C termini the of the protein to to that the Bax is a required for membrane and but that at the N are key to this of the of Bax the Bax to membranes in and the pro-apoptotic activity of Bax in (4.Goping I.S. Gross A. Lavoie J.N. Nguyen M. Jemmerson R. Roth K. Korsmeyer S.J. Shore G.C. J. Cell Biol. 1998; 143: 207-215Crossref PubMed Scopus (548) Google Scholar). of the occurs the N is interaction with the of the that may the or a of interaction with This is with that does not lead to Bax membrane but that a is required to of the sensitized have shown that tBid can function as a for the sensitized Bax but potential other pro-apoptotic Bcl-2 family members as L. A. G. Adams J.M. S. J. 1998; PubMed Scopus Google Scholar), a membrane protein Montessuit S. Antonsson B. Martinou J.C. Biochem. J. 2002; PubMed Scopus Google Scholar), or (19.Epand R.F. Martinou J.C. Montessuit S. Epand R.M. Biochem. J. 2002; 367: 849-855Crossref PubMed Scopus (38) Google Scholar). of data is that the lipid of the Bax does not depend on the of a specific this may at with data that the permeabilization of liposomes on the mitochondria-specific lipid cardiolipin (19.Epand R.F. Martinou J.C. Montessuit S. Epand R.M. Biochem. J. 2002; 367: 849-855Crossref PubMed Scopus (38) Google Scholar, 20.Kuwana T. Mackey M.R. Perkins G. Ellisman M.H. Latterich M. Schneiter R. Green D.R. Newmeyer D.D. Cell. 2002; 111: 331-342Abstract Full Text Full Text PDF PubMed Scopus (1218) Google Scholar). cardiolipin has been shown to be required for pore formation, in Bax activation have not been (19.Epand R.F. Martinou J.C. Montessuit S. Epand R.M. Biochem. J. 2002; 367: 849-855Crossref PubMed Scopus (38) Google Scholar, 20.Kuwana T. Mackey M.R. Perkins G. Ellisman M.H. Latterich M. Schneiter R. Green D.R. Newmeyer D.D. Cell. 2002; 111: 331-342Abstract Full Text Full Text PDF PubMed Scopus (1218) Google Scholar). In we have shown that Bax with lipid membrane surfaces where it undergoes a reversible conformational change that is not by or interactions with a specific The conformational change in Bax a is not this conformational change is reversible lipid membranes are Although of the Bax has been associated with activation of the pro-apoptotic function of it a that is of the of the Bax activation process in Indeed, we have shown that the lipid-induced of the Bax is a for tBid to induce Bax oligomerization and pore formation. that Bax activation can in discrete a that for multiple levels of regulation. of to

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