Quantitative reactivity profiling predicts functional cysteines in proteomes

By E. Weerapana, Chu Wang, G. Simon, Florian Richter, Sagar D. Khare, M. Dillon, D. Bachovchin, K. Mowen, David Baker, B. Cravatt. Nature, 2010

1,518 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/aa9a74eb811e350ac7605fdeeaadaa49855748ca

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In Molecular Biology

1. Shiwei Wang
2. Jianfeng Pei
3. Luhua Lai
4. B. Dickinson
5. Christopher J. Chang

Citations in the corpus

• The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020, methodology): “accelerated by combining the platforms of isoTOP-ABPP with cysteine-reactive ligand libraries [66].”
• CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction (2018, background): “Cysteine usually has the highest nucleophilic reactivity among the natural amino acid residues (7).”
• Chemistry and biology of reactive oxygen species in signaling or stress responses (2011, background): “In addition, recent advances in activity-based protein profiling allow the quantification of nucleophilic, reactive cysteine residues that are more likely to be oxidized by ROS such as H 2 O 2 (ref”
• Target identification with quantitative activity based protein profiling (ABPP) (2017, neutral): “7A and B) [81].”