BAX activation is initiated at a novel interaction site

Evripidis Gavathiotis, Motoshi Suzuki, Marguerite L. Davis, Kenneth Pitter, Gregory H. Bird, Samuel G. Katz, Ho Chou Tu, Hyungjin Kim, Emily H Y Cheng, Nico Tjandra, Loren D. Walensky

Research output: Contribution to journalArticle

478 Citations (Scopus)

Abstract

BAX is a pro-apoptotic protein of the BCL-2 family that is stationed in the cytosol until activated by a diversity of stress stimuli to induce cell death. Anti-apoptotic proteins such as BCL-2 counteract BAX-mediated cell death. Although an interaction site that confers survival functionality has been defined for anti-apoptotic proteins, an activation site has not been identified for BAX, rendering its explicit trigger mechanism unknown. We previously developed stabilized α-helix of BCL-2 domains (SAHBs) that directly initiate BAX-mediated mitochondrial apoptosis. Here we demonstrate by NMR analysis that BIM SAHB binds BAX at an interaction site that is distinct from the canonical binding groove characterized for anti-apoptotic proteins. The specificity of the human BIM-SAHB-BAX interaction is highlighted by point mutagenesis that disrupts functional activity, confirming that BAX activation is initiated at this novel structural location. Thus, we have now defined a BAX interaction site for direct activation, establishing a new target for therapeutic modulation of apoptosis.

Original languageEnglish (US)
Pages (from-to)1076-1081
Number of pages6
JournalNature
Volume455
Issue number7216
DOIs
StatePublished - Oct 23 2008
Externally publishedYes

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Apoptosis Regulatory Proteins
Cell Death
Apoptosis
Mutagenesis
Cytosol
Survival
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Gavathiotis, E., Suzuki, M., Davis, M. L., Pitter, K., Bird, G. H., Katz, S. G., ... Walensky, L. D. (2008). BAX activation is initiated at a novel interaction site. Nature, 455(7216), 1076-1081. https://doi.org/10.1038/nature07396

BAX activation is initiated at a novel interaction site. / Gavathiotis, Evripidis; Suzuki, Motoshi; Davis, Marguerite L.; Pitter, Kenneth; Bird, Gregory H.; Katz, Samuel G.; Tu, Ho Chou; Kim, Hyungjin; Cheng, Emily H Y; Tjandra, Nico; Walensky, Loren D.

In: Nature, Vol. 455, No. 7216, 23.10.2008, p. 1076-1081.

Research output: Contribution to journalArticle

Gavathiotis, E, Suzuki, M, Davis, ML, Pitter, K, Bird, GH, Katz, SG, Tu, HC, Kim, H, Cheng, EHY, Tjandra, N & Walensky, LD 2008, 'BAX activation is initiated at a novel interaction site', Nature, vol. 455, no. 7216, pp. 1076-1081. https://doi.org/10.1038/nature07396
Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG et al. BAX activation is initiated at a novel interaction site. Nature. 2008 Oct 23;455(7216):1076-1081. https://doi.org/10.1038/nature07396
Gavathiotis, Evripidis ; Suzuki, Motoshi ; Davis, Marguerite L. ; Pitter, Kenneth ; Bird, Gregory H. ; Katz, Samuel G. ; Tu, Ho Chou ; Kim, Hyungjin ; Cheng, Emily H Y ; Tjandra, Nico ; Walensky, Loren D. / BAX activation is initiated at a novel interaction site. In: Nature. 2008 ; Vol. 455, No. 7216. pp. 1076-1081.
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