An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway
Open accessAbstract
Pro-apoptotic BAX is a cell fate regulator playing an important role in cellular homeostasis and pathological cell death. BAX is predominantly localized in the cytosol, where it has a quiescent monomer conformation. Following a pro-apoptotic trigger, cytosolic BAX is activated and translocates to the mitochondria to initiate mitochondrial dysfunction and apoptosis. Here, cellular, biochemical, and structural data unexpectedly demonstrate that cytosolic BAX also has an inactive dimer conformation that regulates its activation. The full-length crystal structure of the inactive BAX dimer revealed an asymmetric interaction consistent with inhibition of the N-terminal conformational change of one protomer and the displacement of the C-terminal helix α9 of the second protomer. This autoinhibited BAX dimer dissociates to BAX monomers before BAX can be activated. Our data support a model whereby the degree of apoptosis induction is regulated by the conformation of cytosolic BAX and identify an unprecedented mechanism of cytosolic BAX inhibition.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The text we found for this paper looks like another document, so the self-check wasn’t run.
Cites
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., et al. (2012) · Nature · doi:10.1038/nature11003 · Cited by 7,950 · see citing works
The BCL-2 protein family: opposing activities that mediate cell death
Youle, R. J., & Strasser, A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2308 · Cited by 4,704 · see citing works
Danial, N. N., & Korsmeyer, S. J. (2004) · Cell · doi:10.1016/s0092-8674(04)00046-7 · Cited by 4,651 · see citing works
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
Self-citationABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Souers, A. J., Leverson, J. D., Boghaert, E. R., Ackler, S. L., Catron, N. D., Chen, J., Dayton, B. D., Ding, H., Enschede, S. H., Fairbrother, W. J., et al. (2013) · Nature Medicine · doi:10.1038/nm.3048 · Cited by 3,058 · see citing works
Mitochondria and cell death: outer membrane permeabilization and beyond
Tait, S. W. G., & Green, D. R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2952 · Cited by 2,593 · see citing works
Zhou, H., Rivas, G., & Minton, A. P. (2008) · Annual Review of Biophysics · doi:10.1146/annurev.biophys.37.032807.125817 · Cited by 2,130 · see citing works
Programmed Cell Death in Animal Development and Disease
Fuchs, Y., & Steller, H. (2011) · Cell · doi:10.1016/j.cell.2011.10.033 · Cited by 1,915 · 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
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
Suzuki, M., Youle, R. J., & Tjandra, N. (2000) · Cell · doi:10.1016/s0092-8674(00)00167-7 · Cited by 1,104 · see citing works
Conformation of the Bax C‐terminus regulates subcellular location and cell death
Nechushtan, A., Smith, C. L., Hsu, Y., & Youle, R. J. (1999) · The EMBO Journal · doi:10.1093/emboj/18.9.2330 · Cited by 732 · see citing works
Mechanisms of Action of Bcl-2 Family Proteins
Shamas-Din, A., Kale, J., Leber, B., & Andrews, D. W. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008714 · Cited by 705 · 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
Self-citationBcl-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
Regulated Targeting of BAX to Mitochondria
Goping, I. S., Gross, A., Lavoie, J. N., Nguyen, M., Jemmerson, R., Roth, K. A., Korsmeyer, S. J., & Shore, G. C. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.1.207 · Cited by 611 · see citing works
Stepwise Activation of BAX and BAK by tBID, BIM, and PUMA Initiates Mitochondrial Apoptosis
Kim, H., Tu, H.-C., Ren, D., Takeuchi, O., Jeffers, J. R., Zambetti, G. P., Hsieh, J. J.-D., & Cheng, E. H.-Y. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.030 · Cited by 600 · see citing works
Self-citationA Unified Model of Mammalian BCL-2 Protein Family Interactions at the Mitochondria
Llambi, F., Moldoveanu, T., Tait, S. W. G., Bouchier-Hayes, L., Temirov, J., McCormick, L. L., Dillon, C. P., & Green, D. R. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.10.001 · Cited by 596 · 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
Hsu, Y., & Youle, R. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10777 · Cited by 504 · see citing works
Many players in BCL-2 family affairs
Moldoveanu, T., Follis, A. V., Kriwacki, R. W., & Green, D. R. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.12.006 · Cited by 421 · see citing works
Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis
Annis, M. G., Soucie, E. L., Dlugosz, P. J., Cruz-Aguado, J. A., Penn, L. Z., Leber, B. F., & Andrews, D. W. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600675 · Cited by 377 · see citing works
BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAX
Gavathiotis, E., Reyna, D. E., Davis, M. L., Bird, G. H., & Walensky, L. D. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.10.019 · Cited by 310 · see citing works
Self-citationBcl‐2 changes conformation to inhibit Bax oligomerization
Dlugosz, P. J., Billen, L. P., Annis, M. G., Zhu, W., Zhang, Z., Lin, J., Leber, B. F., & Andrews, D. W. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601126 · Cited by 262 · see citing works
An interconnected hierarchical model of cell death regulation by the BCL-2 family
Chen, H.-C., Kanai, M., Inoue-Yamauchi, A., Tu, H.-C., Huang, Y., Ren, D., Kim, H., Takeda, S., Reyna, D. E., Chan, P. M., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3236 · Cited by 249 · see citing works
Self-citationSchellenberg, 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
Structural Model of Active Bax at the Membrane
Bleicken, S., Jeschke, G., Stegmueller, C., Salvador-Gallego, R., García-Sáez, A. J., & Bordignon, E. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.09.022 · Cited by 227 · see citing works
Prolyl isomerase Pin1 in cancer
Lu, Z., & Hunter, T. R. (2014) · Cell Research · doi:10.1038/cr.2014.109 · Cited by 203 · see citing works
Bax dimerizes via a symmetric BH3:groove interface during apoptosis
Dewson, G., Ma, S., Frederick, P., Hockings, C., Tan, I., Kratina, T., & Kluck, R. M. (2012) · Cell Death & Differentiation · doi:10.1038/cdd.2011.138 · Cited by 189 · see citing works
The multidomain proapoptotic molecules Bax and Bak are directly activated by heat
Pagliari, L. J., Kuwana, T., Bonzon, C., Newmeyer, D. D., Tu, S. S., Beere, H. M., & Green, D. R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506712102 · Cited by 185 · see citing works
Walensky, L. D., & Gavathiotis, E. (2011) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2011.08.009 · Cited by 173 · see citing works
Self-citationDirect and selective small-molecule activation of proapoptotic BAX
Gavathiotis, E., Reyna, D. E., Bellairs, J. A., Leshchiner, E. S., & Walensky, L. D. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.995 · Cited by 169 · see citing works
Self-citationBcl‐xL sequesters its C‐terminal membrane anchor in soluble, cytosolic homodimers
Jeong, S., Gaume, B. R., Lee, Y.-J., Hsu, Y., Ryu, S., Yoon, S., & Youle, R. J. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600225 · Cited by 162 · see citing works
Conformational control of Bax localization and apoptotic activity by Pro168
Schinzel, A. C., Kaufmann, T., Schüler, M., Martinalbo, J., Grubb, D. R., & Borner, C. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200309013 · Cited by 146 · see citing works
Inhibition of Pro-Apoptotic BAX by a Noncanonical Interaction Mechanism
Barclay, L. A., Wales, T. E., Garner, T. P., Wachter, F., Lee, S., Guerra, R. M., Stewart, M. L., Braun, C. R., Bird, G. H., Gavathiotis, E., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.01.014 · Cited by 134 · see citing works
Self-citationShen, Z.-J., Esnault, S. J., Schinzel, A. C., Borner, C., & Malter, J. S. (2009) · Nature Immunology · doi:10.1038/ni.1697 · Cited by 104 · see citing works
Düßmann, H., Rehm, M., Concannon, C. G., Anguissola, S., Würstle, M. L., Kacmar, S., Völler, P., Huber, H. J., & Prehn, J. H. M. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.123 · Cited by 103 · see citing works
BCL-XL Dimerization by Three-dimensional Domain Swapping
O’Neill, J., Manion, M. K., Maguire, B. C., & Hockenbery, D. M. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.11.032 · Cited by 98 · see citing works
Distinct BimBH3 (BimSAHB) Stapled Peptides for Structural and Cellular Studies
Bird, G. H., Gavathiotis, E., LaBelle, J. L., Katz, S. G., & Walensky, L. D. (2013) · ACS Chemical Biology · doi:10.1021/cb4003305 · Cited by 96 · see citing works
Self-citationDing, J., Zhang, Z., Roberts, G. J., Falcone, M., Miao, Y., Shao, Y., Zhang, X. C., Andrews, D. W., & Lin, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.148361 · Cited by 77 · see citing works
Ding, J., Mooers, B. H. M., Zhang, Z., Kale, J., Falcone, D., Mcnichol, J., Huang, B., Zhang, X. C., Xing, C., Andrews, D. W., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.552562 · Cited by 76 · see citing works
Vogel, S., Raulf, N., Bregenhorn, S., Biniossek, M. L., Maurer, U., Czabotar, P. E., & Borner, C. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.248906 · Cited by 33 · see citing works
Uchime, O., Dai, Z., Biris, N., Lee, D. E., Sidhu, S. S., Li, S., Lai, J. R., & Gavathiotis, E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.680918 · Cited by 30 · see citing works
Self-citationLee, E. F., Dewson, G., Smith, B. J., et al. (2011) · Structure · doi:10.1016/j.str.2011.07.015 · Cited by 26 · 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
Self-citationBCL-2 family proteins: changing partners in the dance towards death
Kale, J., Osterlund, E. J., & Andrews, D. W. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.186 · Cited by 1,574 · see citing works
Bleicken, S., Hantusch, A., Das, K. K., Frickey, T., & Garcia-Saez, A. J. (2017) · Nature Communications · doi:10.1038/s41467-017-00086-6 · Cited by 70 · see citing works
- Authors
- Garner, T. P., Reyna, D. E., Priyadarshi, A., Chen, H.-C., Li, S., Wu, Y., Ganesan, Y. T., Malashkevich, V. N., Cheng, E. H., & Gavathiotis, E.
- Affiliations
- Albert Einstein College of Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of California San Diego (US)
- Corresponding author
- Gavathiotis, Evripidis
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 63
- Issue
- 3
- Pages
- 485-497
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4975667
- OpenAlex
- W2463785236
- Cited by
- 108
- References
- 46
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 10 · 2023: 14 · 2022: 10 · 2021: 16 · 2020: 7 · 2019: 10 · 2018: 11 · 2017: 8 · 2016: 2
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-10-20)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Sidney Kimmel Foundation for Cancer Research
- Sidney Kimmel Foundation
- National Institutes of Health (1s10od016305-01a1, UL1TR001073, CA013330)
- National Heart, Lung, and Blood Institute (R00HL095929)
- National Cancer Institute (R01CA178394, R01CA125562, P30CA008748, P30CA013330)
- National Institute of General Medical Sciences (R01GM020501, P41GM111244)
- National Institute of Allergy and Infectious Diseases (R01AI101436, U19AI117905)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- Bax, autoinhibition, apoptosis, Bax activation, mitochondrial translocation, crystal structure, conformational change, Bcl-2 family proteins, protein dimerization
- MeSH terms
- Protein Conformation, alpha-Helical, Animals, Binding Sites, Cells, Cultured, Cytosol, Fibroblasts, Humans, Models, Molecular, Protein Binding, Structure-Activity Relationship, Transfection, Signal Transduction, Apoptosis, Crystallography, X-Ray, bcl-2-Associated X Protein, Mice, Protein Interaction Domains and Motifs, Protein Multimerization
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
