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- Title
A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles.
- Authors
Wang, Chu; Weerapana, Eranthie; Blewett, Megan M; Cravatt, Benjamin F
- 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.
- Subjects
ELECTROPHILES; LIPIDS; QUANTITATIVE research; OXIDATIVE stress; JNK mitogen-activated protein kinases; CYSTEINE
- Publication
Nature Methods, 2014, Vol 11, Issue 1, p79
- ISSN
1548-7091
- Publication type
Article
- DOI
10.1038/nmeth.2759