A Chemoproteomic Platform to Quantitatively Map Targets of Lipid-derived Electrophiles

Overview

Journal Nat Methods

Specialties Biomedical Engineering
Pathology

Date 2013 Dec 3

PMID 24292485

Citations 134

Authors

Chu Wang

Eranthie Weerapana

Megan M Blewett

Benjamin F Cravatt

Affiliations

Soon will be listed here.

Abstract

Cells produce electrophilic products with the potential to modify and affect the function of proteins. Chemoproteomic methods have provided a means to qualitatively inventory proteins targeted by endogenous electrophiles; however, ascertaining the potency and specificity of these reactions to identify the sites in the proteome that are most sensitive to electrophilic modification requires more quantitative methods. Here we describe a competitive activity-based profiling method for quantifying the reactivity of electrophilic compounds against >1,000 cysteines in parallel in the human proteome. Using this approach, we identified a select set of proteins that constitute 'hot spots' for modification by various lipid-derived electrophiles, including the oxidative stress product 4-hydroxy-2-nonenal (HNE). We show that one of these proteins, ZAK kinase, is labeled by HNE on a conserved, active site-proximal cysteine and that the resulting enzyme inhibition creates a negative feedback mechanism that can suppress the activation of JNK pathways normally induced by oxidative stress.

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