Quantitative reactivity profiling predicts functional cysteines in proteomes

Eranthie Weerapana, Chu Wang, Gabriel M. Simon, Florian Richter, Sagar Khare, Myles B. D. Dillon, Daniel A. Bachovchin, Kerri Mowen, David Baker and Benjamin F. Cravatt ()
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Eranthie Weerapana: The Skaggs Institute for Chemical Biology, The Scripps Research Institute
Chu Wang: The Skaggs Institute for Chemical Biology, The Scripps Research Institute
Gabriel M. Simon: The Skaggs Institute for Chemical Biology, The Scripps Research Institute
Florian Richter: University of Washington
Sagar Khare: University of Washington
Myles B. D. Dillon: The Scripps Research Institute
Daniel A. Bachovchin: The Skaggs Institute for Chemical Biology, The Scripps Research Institute
Kerri Mowen: The Scripps Research Institute
David Baker: University of Washington
Benjamin F. Cravatt: The Skaggs Institute for Chemical Biology, The Scripps Research Institute

Nature, 2010, vol. 468, issue 7325, 790-795

Abstract: Abstract 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.

Date: 2010
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DOI: 10.1038/nature09472

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