Quantitative reactivity profiling predicts functional cysteines in proteomes
Open accessAbstract
Cysteine is the most intrinsically nucleophilic amino acid in proteins, where its reactivity is tuned to perform diverse biochemical functions. The absence of a consensus sequence that defines functional cysteines in proteins has hindered their discovery and characterization. Here we describe a proteomics method to profile quantitatively the intrinsic reactivity of cysteine residues en masse directly in native biological systems. Hyper-reactivity was a rare feature among cysteines and it was found to specify a wide range of activities, including nucleophilic and reductive catalysis and sites of oxidative modification. Hyper-reactive cysteines were identified in several proteins of uncharacterized function, including a residue conserved across eukaryotic phylogeny that we show is required for yeast viability and is involved in iron-sulphur protein biogenesis. We also demonstrate that quantitative reactivity profiling can form the basis for screening and functional assignment of cysteines in computationally designed proteins, where it discriminated catalytically active from inactive cysteine hydrolase designs.
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In the first isoTOP-ABPP reports, an iodoacetamide probe carrying an alkyne handle was used to identify hyper-reactive cysteines across the proteome.
“In the first reports of the isoTOP-ABPP (isotopic tandem orthogonal proteolysis–activity-based protein profiling) approach, an iodoacetamide probe functionalized with an alkyne handle was used to identify hyper-reactive cysteines across the proteome176,177”
From Advances in covalent drug discovery (2022) · cites this paper as [177]
Cysteine hyper-reactivity predicts cysteine function in catalysis and at post-translational modification sites.
“Using this approach, it was discovered that the hyper-reactivity of cysteines predicts their functionality in catalysis and at sites of post-translational modifications177.”
From Advances in covalent drug discovery (2022) · cites this paper as [177]
Electrophilic natural products represent a vastly underexplored subset of natural products from which molecular glues can originate, and such species could have unique and positive attributes owing to their potential for covalent bond formation.
“Electrophilic natural products represent a vastly underexplored subset of natural products from which molecular glues can originate, and such species could have unique and positive attributes owing to their potential for covalent bond formation16.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [16]
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- Authors
- Weerapana, E., Wang, C., Simon, G. M., Richter, F., Khare, S., Dillon, M. B. D., Bachovchin, D. A., Mowen, K., Baker, D., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Cravatt, Benjamin F.
- ORCID
- Venue
- Nature
- Published
- 2010-11-17
- Volume
- 468
- Issue
- 7325
- Pages
- 790-795
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3058684
- OpenAlex
- W2018339027
- Cited by
- 1,684
- References
- 50
- Citations by year
- 2026: 108 · 2025: 126 · 2024: 128 · 2023: 162 · 2022: 116 · 2021: 138 · 2020: 122 · 2019: 156 · 2018: 114 · 2017: 112 · 2016: 88 · 2015: 72 · 2014: 76 · 2013: 55 · 2012: 66
- FWCI
- 21.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Mental Health (U54MH084512, MH-084512)
- National Cancer Institute (CA-087660, R37CA087660, R01CA087660)
- National Institute of General Medical Sciences (R01GM090294, R01GM085117)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- nucleophilic catalysis, reductive catalysis, oxidative modification, activity-based probes, yeast viability, protein microenvironment
- MeSH terms
- Animals, Cysteine, Humans, Hydrolases, Iron-Sulfur Proteins, Liver, Myocardium, Nuclear Proteins, Oxidation-Reduction, Protein-Arginine N-Methyltransferases, Protein Hydrolysates, Proteins, Repressor Proteins, Saccharomyces cerevisiae, Protein Engineering, Conserved Sequence, Proteome, Saccharomyces cerevisiae Proteins, Proteomics, Cell Line, Tumor, Mice, Biocatalysis
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