Cited by 111Cell death mechanisms and regulationMitochondrial Function and PathologyAutophagy in Disease and Therapy

Inhibition of Bak Activation by VDAC2 Is Dependent on the Bak Transmembrane Anchor

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Lazarou, Michael, Stojanovski, Diana, Frazier, Ann E., Kotevski, Aneta, Dewson, Grant, Craigen, William J., Kluck, Ruth M., Vaux, David L. +1 more·2010·Journal of Biological Chemistry

Abstract

Bax and Bak are pro-apoptotic factors that are required for cell death by the mitochondrial or intrinsic pathway. Bax is found in an inactive state in the cytosol and upon activation is targeted to the mitochondrial outer membrane where it releases cytochrome c and other factors that cause caspase activation. Although Bak functions in the same way as Bax, it is constitutively localized to the mitochondrial outer membrane. In the membrane, Bak activation is inhibited by the voltage-dependent anion channel isoform 2 (VDAC2) by an unknown mechanism. Using blue native gel electrophoresis, we show that in healthy cells endogenous inactive Bak exists in a 400-kDa complex that is dependent on the presence of VDAC2. Activation of Bak is concomitant with its release from the 400-kDa complex and the formation of lower molecular weight species. Furthermore, substitution of the Bak transmembrane anchor with that of the mitochondrial outer membrane tail-anchored protein hFis1 prevents association of Bak with the VDAC2 complex and increases the sensitivity of cells to an apoptotic stimulus. Our results suggest that VDAC2 interacts with the hydrophobic tail of Bak to sequester it in an inactive state in the mitochondrial outer membrane, thereby raising the stimulation threshold necessary for permeabilization of the mitochondrial outer membrane and cell death.

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  • BAK constitutively resides at the OMM, where it inserts within the lipid bilayer via its hydrophobic C-terminal α9 helix upon interaction with VDAC2.

    “In contrast, BAK constitutively resides at the OMM, where it inserts within the lipid bilayer via its hydrophobic C-terminal α9 helix upon interaction with voltage dependent anion channel 2 (VDAC2) [51–54].”

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  1. Brooks, C., Wei, Q., Feng, L., Dong, G., Tao, Y., Mei, L., Xie, Z. J., and Dong, Z. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 11649 -11654
  2. Hsu, Y. T., Wolter, K. G., and Youle, R. J. (1997) Proc. Natl. Acad. Sci.
  3. Pagliari, L. J., Kuwana, T., Bonzon, C., Newmeyer, D. D., Tu, S., Beere, H. M., and Green, D. R. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 17975-17980
  4. Bayrhuber, M., Meins, T., Habeck, M., Becker, S., Giller, K., Villinger, S., Vonrhein, C., Griesinger, C., Zweckstetter, M., and Zeth, K. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 15370 -15375
  5. Ujwal, R., Cascio, D., Colletier, J. P., Faham, S., Zhang, J., Toro, L., Ping, P., and Abramson, J. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 17742-17747

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Authors
Lazarou, M., Stojanovski, D., Frazier, A. E., Kotevski, A., Dewson, G., Craigen, W. J., Kluck, R. M., Vaux, D. L., & Ryan, M. T.
Affiliations
  • La Trobe University (AU)
  • Walter and Eliza Hall Institute of Medical Research (AU)
  • Baylor College of Medicine (US)
Corresponding author
Ryan, Michael T.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2010-11
Volume
285
Issue
47
Pages
36876-36883
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2063418623
Cited by
111
References
55
Citations by year
2026: 9 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 11 · 2016: 10 · 2015: 10 · 2014: 6 · 2013: 6 · 2012: 7
FWCI
2.99
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Bank (Australian Catholic University) (submittedVersion)
Funders
  • La Trobe University
  • Centre of Excellence for Coherent X-Ray Science, Australian Research Council
  • Medical Research Council
  • Australian Research Council
  • National Health and Medical Research Council
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
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Bak, VDAC2, Bax, apoptosis, mitochondrial outer membrane permeabilization, tail-anchored proteins, cytochrome c release, mitochondrial apoptosis
MeSH terms
Animals, Cell Membrane Permeability, Cells, Cultured, Embryo, Mammalian, Fibroblasts, HeLa Cells, Humans, Membrane Proteins, Immunoblotting, Apoptosis, Mice, Knockout, Mitochondrial Proteins, Voltage-Dependent Anion Channel 2, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mitochondrial Membranes, Mice

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