BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAX

Evripidis Gavathiotis; Denis E. Reyna; Marguerite L. Davis; Gregory H. Bird; Loren D. Walensky

doi:10.1016/j.molcel.2010.10.019

BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAX

Evripidis Gavathiotis, Denis E. Reyna, Marguerite L. Davis, Gregory H. Bird, Loren D. Walensky

Research output: Contribution to journal › Article › peer-review

250 Scopus citations

Abstract

BAX is a proapoptotic BCL-2 family member that lies dormant in the cytosol until converted into a killer protein in response to cellular stress. Having recently identified the elusive trigger site for direct BAX activation, we now delineate by NMR and biochemical methods the essential allosteric conformational changes that transform ligand-triggered BAX into a fully activated monomer capable of propagating its own activation. Upon BAX engagement by a triggering BH3 helix, the unstructured loop between α helices 1 and 2 is displaced, the carboxy-terminal helix 9 is mobilized for membrane translocation, and the exposed BAX BH3 domain propagates the death signal through an autoactivating interaction with the trigger site of inactive BAX monomers. Our structure-activity analysis of this seminal apoptotic process reveals pharmacologic opportunities to modulate cell death by interceding at key steps of the BAX activation pathway.

Original language	English (US)
Pages (from-to)	481-492
Number of pages	12
Journal	Molecular Cell
Volume	40
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2010.10.019
State	Published - Nov 12 2010
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2010.10.019

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title = "BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAX",

abstract = "BAX is a proapoptotic BCL-2 family member that lies dormant in the cytosol until converted into a killer protein in response to cellular stress. Having recently identified the elusive trigger site for direct BAX activation, we now delineate by NMR and biochemical methods the essential allosteric conformational changes that transform ligand-triggered BAX into a fully activated monomer capable of propagating its own activation. Upon BAX engagement by a triggering BH3 helix, the unstructured loop between α helices 1 and 2 is displaced, the carboxy-terminal helix 9 is mobilized for membrane translocation, and the exposed BAX BH3 domain propagates the death signal through an autoactivating interaction with the trigger site of inactive BAX monomers. Our structure-activity analysis of this seminal apoptotic process reveals pharmacologic opportunities to modulate cell death by interceding at key steps of the BAX activation pathway.",

author = "Evripidis Gavathiotis and Reyna, {Denis E.} and Davis, {Marguerite L.} and Bird, {Gregory H.} and Walensky, {Loren D.}",

note = "Funding Information: We thank E. Smith for editorial and graphics assistance, N. Tjandra and M. Suzuki for BAX NMR assignments and helpful discussions, C. Turner of the MIT/Harvard Center for Magnetic Resonance and S. Pochapsky of the Brandeis University Nuclear Magnetic Resonance Facility for technical advice, and S. Gygi and J. Mintseris of Harvard Medical School for mass spectrometry analysis. This work was supported by National Institutes of Health (NIH) grant 2R01CA050239, an American Society of Hematology Junior Faculty Scholar Award, and a grant from the William Lawrence Children's Foundation to L.D.W.; and an American Heart Association Founders Affiliate Scientist Development Grant to E.G. We also thank the LaTorre family for their generous support of D.E.R. ",

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AU - Walensky, Loren D.

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BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAX

Abstract

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