Integration and Oligomerization of Bax Protein in Lipid Bilayers Characterized by Single Molecule Fluorescence Study
Open accessAbstract
Bax is a pro-apoptotic Bcl-2 family protein. The activated Bax translocates to mitochondria, where it forms pore and permeabilizes the mitochondrial outer membrane. This process requires the BH3-only activator protein (i.e. tBid) and can be inhibited by anti-apoptotic Bcl-2 family proteins such as Bcl-xL. Here by using single molecule fluorescence techniques, we studied the integration and oligomerization of Bax in lipid bilayers. Our study revealed that Bax can bind to lipid membrane spontaneously in the absence of tBid. The Bax pore formation undergoes at least two steps: pre-pore formation and membrane insertion. The activated Bax triggered by tBid or BH3 domain peptide integrates on bilayers and tends to form tetramers, which are termed as pre-pore. Subsequent insertion of the pre-pore into membrane is highly dependent on the composition of cardiolipin in lipid bilayers. Bcl-xL can translocate Bax from membrane to solution and inhibit the pore formation. The study of Bax integration and oligomerization at the single molecule level provides new evidences that may help elucidate the pore formation of Bax and its regulatory mechanism in apoptosis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mitochondrial size and shape as well as lipid composition can influence the likelihood of mitochondria to undergo irreversible MOMP.
“Finally, it is becoming increasingly evident that mitochondrial size and shape [139–141] as well as lipid composition [142, 143] can influence the likelihood of mitochondria to undergo irreversible MOMP.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [142]
Cites
Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988 · see citing works
Luo, X., Budihardjo, I., Zou, H., Slaughter, C., & Wang, X. (1998) · Cell · doi:10.1016/s0092-8674(00)81589-5 · Cited by 3,626 · see citing works
Bcl-2 functions in an antioxidant pathway to prevent apoptosis
Hockenbery, D. M., Oltvai, Z. N., Yin, X., Milliman, C. L., & Korsmeyer, S. J. (1993) · Cell · doi:10.1016/0092-8674(93)80066-n · Cited by 3,420 · see citing works
The Pathophysiology of Mitochondrial Cell Death
Green, D. R., & Kroemer, G. (2004) · Science · doi:10.1126/science.1099320 · Cited by 3,416 · see citing works
bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death
Boise, L., González‐García, M., Postema, C. E., Ding, L., Lindsten, T., Turka, L. A., Mao, X., Núñez, G., & Thompson, C. B. (1993) · Cell · doi:10.1016/0092-8674(93)90508-n · Cited by 3,089 · see citing works
A practical guide to single-molecule FRET
Roy, R., Hohng, S., & Ha, T. (2008) · Nature Methods · doi:10.1038/nmeth.1208 · Cited by 2,157 · see citing works
Movement of Bax from the Cytosol to Mitochondria during Apoptosis
Wolter, K. G., Hsu, Y., Smith, C. L., Nechushtan, A., Xi, X., & Youle, R. J. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.139.5.1281 · Cited by 1,809 · see citing works
Bid, Bax, and Lipids Cooperate to Form Supramolecular Openings in the Outer Mitochondrial Membrane
Kuwana, T., Mackey, M. R., Perkins, G. A., Ellisman, M. H., Latterich, M., Schneiter, R., Green, D. R., & Newmeyer, D. D. (2002) · Cell · doi:10.1016/s0092-8674(02)01036-x · Cited by 1,480 · see citing works
Chipuk, J. E., Moldoveanu, T., Llambi, F., Parsons, M. J., & Green, D. R. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.025 · Cited by 1,432 · see citing works
Desagher, S., Osen‐Sand, A., Nichols, A. C., Eskes, R., Montessuit, S., Lauper, S., Maundrell, K., Antonsson, B. E., & Martinou, J. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.144.5.891 · Cited by 1,260 · see citing works
Bid Induces the Oligomerization and Insertion of Bax into the Outer Mitochondrial Membrane
Eskes, R., Desagher, S., Antonsson, B. E., & Martinou, J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.3.929-935.2000 · Cited by 1,190 · see citing works
Kuwana, T., Bouchier-Hayes, L., Chipuk, J. E., Bonzon, C., Sullivan, B. A., Green, D. R., & Newmeyer, D. D. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.02.003 · Cited by 1,185 · see citing works
BAX activation is initiated at a novel interaction site
Gavathiotis, E., Suzuki, M., Davis, M. L., Pitter, K., Bird, G. H., Katz, S. G., Tu, H.-C., Kim, H., Cheng, E. H.-Y., Tjandra, N., et al. (2008) · Nature · doi:10.1038/nature07396 · Cited by 700 · see citing works
Bcl-xL Retrotranslocates Bax from the Mitochondria into the Cytosol
Edlich, F., Banerjee, S., Suzuki, M., Cleland, M. M., Arnoult, D., Wang, C., Neutzner, A., Tjandra, N., & Youle, R. J. (2011) · Cell · doi:10.1016/j.cell.2011.02.034 · Cited by 630 · see citing works
Czabotar, P. E., Westphal, D., Dewson, G., Ma, S., Hockings, C., Fairlie, W. D., Lee, E. F., Yao, S., Robin, A. Y., Smith, B. J., et al. (2013) · Cell · doi:10.1016/j.cell.2012.12.031 · Cited by 573 · see citing works
Lovell, J. F., Billen, L. P., Bindner, S., Shamas‐Din, A., Fradin, C., Leber, B. F., & Andrews, D. W. (2008) · Cell · doi:10.1016/j.cell.2008.11.010 · Cited by 564 · see citing works
Zha, J., Weiler, S., Oh, K. J., Wei, M. C., & Korsmeyer, S. J. (2000) · Science · doi:10.1126/science.290.5497.1761 · Cited by 559 · see citing works
Hsu, Y., & Youle, R. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10777 · Cited by 504 · see citing works
Membrane Remodeling Induced by the Dynamin-Related Protein Drp1 Stimulates Bax Oligomerization
Montessuit, S., Somasekharan, S. P., Terrones, O., Lucken‐Ardjomande, S., Herzig, S., Schwarzenbacher, R., Manstein, D. J., Bossy‐Wetzel, E., Basáñez, G., Meda, P., et al. (2010) · Cell · doi:10.1016/j.cell.2010.08.017 · Cited by 422 · see citing works
Bcl-XL Inhibits Membrane Permeabilization by Competing with Bax
Billen, L. P., Kokoski, C., Lovell, J. F., Leber, B. F., & Andrews, D. W. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060147 · Cited by 312 · see citing works
Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis
Schug, Z. T., & Gottlieb, E. (2009) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2009.05.004 · Cited by 259 · see citing works
Schellenberg, B., Wang, P., Keeble, J. A., Rodriguez-Enriquez, R., Walker, S., Owens, T. W., Foster, F., Tanianis-Hughes, J., Brennan, K., Streuli, C. H., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.12.022 · Cited by 237 · see citing works
Yethon, J. A., Epand, R. F., Leber, B. F., Epand, R. M., & Andrews, D. W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306289200 · Cited by 203 · see citing works
Tan, C., Dlugosz, P. J., Peng, J., Zhang, Z., Lapolla, S. M., Plafker, S. M., Andrews, D. W., & Lin, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602374200 · Cited by 151 · see citing works
Contributions to Bax insertion and oligomerization of lipids of the mitochondrial outer membrane
Lucken‐Ardjomande, S., Montessuit, S., & Martinou, J. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.9 · Cited by 134 · see citing works
Ortiz, A., Killian, J. A., Verkleij, A. J., & Wilschut, J. (1999) · Biophysical Journal · doi:10.1016/s0006-3495(99)77041-4 · Cited by 133 · see citing works
Membrane-Insertion Fragments of Bcl-xL, Bax, and Bid
García‐Sáez, A. J., Mingarro, I., Pérez‐Payá, E., & Salgado, J. (2004) · Biochemistry · doi:10.1021/bi036044c · Cited by 130 · see citing works
The C-terminal helix of Bcl-xL mediates Bax retrotranslocation from the mitochondria
Todt, F., Cakir, Z., Reichenbach, F., Youle, R. J., & Edlich, F. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.131 · Cited by 129 · see citing works
tBid Undergoes Multiple Conformational Changes at the Membrane Required for Bax Activation
Shamas‐Din, A., Bindner, S., Zhu, W., Zaltsman, Y., Campbell, C. J. V., Gross, A., Leber, B. F., Andrews, D. W., & Fradin, C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.482109 · Cited by 101 · see citing works
Kushnareva, Y., Andreyev, A. Y., Kuwana, T., & Newmeyer, D. D. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001394 · Cited by 91 · see citing works
Three-dimensional structure of Bax-mediated pores in membrane bilayers
Xu, X.-P., Zhai, D., Kim, E., Swift, M., Reed, J. C., Volkmann, N., & Hanein, D. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.210 · Cited by 79 · see citing works
Emerging roles of lipids in BCL-2 family-regulated apoptosis
Zhang, T., & Saghatelian, A. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.03.001 · Cited by 72 · see citing works
Involvement of cardiolipin in tBID-induced activation of BAX during apoptosis
Raemy, E., & Martinou, J. (2013) · Chemistry and Physics of Lipids · doi:10.1016/j.chemphyslip.2013.12.002 · Cited by 59 · see citing works
Fluorescence detection of the movement of single KcsA subunits reveals cooperativity
Blunck, R., McGuire, H., Hyde, H. C., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807056106 · Cited by 57 · see citing works
Membrane perturbations induced by the apoptotic Bax protein
EPAND, R. F., Martinou, J., Montessuit, S., et al. (2002) · Biochemical Journal · doi:10.1042/bj20020986 · Cited by 44 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
- Authors
- Luo, L., Yang, J., & Liu, D.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shanghai Institute of Planned Parenthood Research (CN)
- Corresponding author
- Liu, Dongxiang
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 289
- Issue
- 46
- Pages
- 31708-31718
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4231651
- OpenAlex
- W2017453569
- Cited by
- 18
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 1
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Bax, Bcl-2 family proteins, mitochondrial outer membrane permeabilization, pore formation, oligomerization, tBid, BH3 domain, Bcl-xL, cardiolipin, apoptosis, membrane insertion
- MeSH terms
- Bcl-2-Like Protein 11, Cardiolipins, Cell Membrane, Gene Expression Regulation, Humans, Lipid Bilayers, Membrane Proteins, Mitochondria, Protein Binding, Proto-Oncogene Proteins, Recombinant Proteins, Apoptosis, Protein Structure, Tertiary, Fluorescence Resonance Energy Transfer, bcl-2 Homologous Antagonist-Killer Protein, Apoptosis Regulatory Proteins, bcl-X Protein, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review