Journal
NATURE METHODS
Volume 11, Issue 1, Pages 79-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NMETH.2759
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Funding
- US National Institutes of Health (NIH) [CA087660]
- NIH/NIEHS [K99ES020851]
- Pfizer Postdoctoral Fellowship
- US National Science Foundation predoctoral fellowship
- Skaggs Institute for Chemical Biology
- NATIONAL CANCER INSTITUTE [R37CA087660, R01CA087660] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [K99ES020851] Funding Source: NIH RePORTER
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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-hydroxy2- nonenal (HNEHNEHNE). We show that one of these proteins, ZAK kinase, is labeled by HNEHNEHNE 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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