Dataset Information

Covalent Inhibition of Pro-Apoptotic BAX

ABSTRACT: BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). Here, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate BAX activity. We identified covalent BAX inhibitor 1 (CBI1) as a compound that selectively derivatizes BAX at C126 and inhibits BAX activation by the physiologic ligand tBID and point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit BAX by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. Hydrogen deuterium exchange mass spectrometry (HDX MS) showed that CBI1 derivatization of BAX C126 reversed the conformational changes caused by the auto-activating mutant F116A These data inform a pharmacologic strategy for blocking apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: John R. Engen

LAB HEAD: John R. Engen

PROVIDER: PXD040917 | Pride | 2024-01-19

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	1_BAX_WT_DMSO_10min_1.raw.zip	Raw
	1_BAX_WT_DMSO_10min_2.raw.zip	Raw
	1_BAX_WT_DMSO_10sec_1.raw.zip	Raw
	1_BAX_WT_DMSO_10sec_2.raw.zip	Raw
	1_BAX_WT_DMSO_1min_1.raw.zip	Raw

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Publications

Covalent inhibition of pro-apoptotic BAX.

McHenry Matthew W MW Shi Peiwen P Camara Christina M CM Cohen Daniel T DT Rettenmaier T Justin TJ Adhikary Utsarga U Gygi Micah A MA Yang Ka K Gygi Steven P SP Wales Thomas E TE Engen John R JR Wells James A JA Walensky Loren D LD

Nature chemical biology 20240117 8

BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). In this study, we ...[more]

PMID: 38233584

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