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Nat Methods. 2014 Jan;11(1):79-85. doi: 10.1038/nmeth.2759. Epub 2013 Dec 1.

A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles.

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1] The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA. [2] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.


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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