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

485 Scopus citations

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

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this

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., & Walensky, L. D. (2008). BAX activation is initiated at a novel interaction site. Nature, 455(7216), 1076-1081. https://doi.org/10.1038/nature07396