Cited by 383Cell death mechanisms and regulationChemical Synthesis and AnalysisMitochondrial Function and Pathology

A Stapled BID BH3 Helix Directly Binds and Activates BAX

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Walensky, Loren D., Pitter, Kenneth, Morash, Joel, Oh, Kyoung Joon, Barbuto, Scott, Fisher, Jill, Smith, Eric, Verdine, Gregory L. +1 more·2006·Molecular Cell

Abstract

BAX is a multidomain proapoptotic BCL-2 family protein that resides in the cytosol until activated by an incompletely understood trigger mechanism, which facilitates BAX translocation to mitochondria and downstream death events. Whether BAX is activated by direct contact with select BH3-only members of the BCL-2 family is highly debated. Here we detect and quantify a direct binding interaction between BAX and a hydrocarbon-stapled BID BH3 domain, which triggers the functional activation of BAX at nanomolar doses in vitro. Chemical reinforcement of BID BH3 alpha helicity was required to reveal the direct BID BH3-BAX association. We confirm the specificity of this BH3 interaction by characterizing a stapled BAD BH3 peptide that interacts with antiapoptotic BCL-X(L) but does not bind or activate BAX. We further demonstrate that membrane targeting of stapled BID BH3 optimizes its ability to activate BAX, supporting a model in which BID directly engages BAX to trigger mitochondrial apoptosis.

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Crossref · 10.1016/j.molcel.2006.08.020

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Authors
Walensky, L. D., Pitter, K., Morash, J., Oh, K. J., Barbuto, S., Fisher, J., Smith, E., Verdine, G. L., & Korsmeyer, S. J.
Affiliations
  • Boston Children's Hospital (US)
  • Howard Hughes Medical Institute (US)
  • Harvard University (US)
Corresponding author
Walensky, Loren D.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2006-10
Volume
24
Issue
2
Pages
199-210
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2000011855
Cited by
383
References
52
Citations by year
2026: 3 · 2025: 8 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 10 · 2020: 18 · 2019: 17 · 2018: 11 · 2017: 18 · 2016: 18 · 2015: 27 · 2014: 20 · 2013: 32 · 2012: 25
FWCI
11.55
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (K08HL074049)
  • National Cancer Institute (P01CA092625, R37CA050239)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Bax, Bid, BH3-only proteins, Bcl-2 family proteins, hydrocarbon-stapled peptides, protein-protein interaction, Bax activation, mitochondrial apoptosis, Bcl-xL, membrane targeting
MeSH terms
Amino Acid Sequence, Cell Membrane, Dose-Response Relationship, Drug, Humans, Liposomes, Molecular Sequence Data, Peptides, Protein Binding, Apoptosis, Sequence Homology, Amino Acid, Jurkat Cells, Protein Transport, bcl-X Protein, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein

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