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A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles
Open accessAbstract
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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Metadata
- Authors
- Wang, C., Weerapana, E., Blewett, M. M., & Cravatt, B. F.
- Venue
- Nature Methods
- Published
- 2013-12-01
- Volume
- 11
- Issue
- 1
- Pages
- 79-85
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- OpenAlex
- W2126593560
- Cited by
- 300
- References
- 1
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- green
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