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Quantitative reactivity profiling predicts functional cysteines in proteomes

Author

Listed:
  • Eranthie Weerapana

    (The Skaggs Institute for Chemical Biology, The Scripps Research Institute
    The Scripps Research Institute)

  • Chu Wang

    (The Skaggs Institute for Chemical Biology, The Scripps Research Institute
    The Scripps Research Institute)

  • Gabriel M. Simon

    (The Skaggs Institute for Chemical Biology, The Scripps Research Institute
    The Scripps Research Institute)

  • Florian Richter

    (University of Washington
    Interdisciplinary Program in Biomolecular Structure and Design, University of Washington)

  • Sagar Khare

    (University of Washington
    Howard Hughes Medical Institute, University of Washington)

  • Myles B. D. Dillon

    (The Scripps Research Institute)

  • Daniel A. Bachovchin

    (The Skaggs Institute for Chemical Biology, The Scripps Research Institute
    The Scripps Research Institute)

  • Kerri Mowen

    (The Scripps Research Institute)

  • David Baker

    (University of Washington
    Interdisciplinary Program in Biomolecular Structure and Design, University of Washington
    Howard Hughes Medical Institute, University of Washington)

  • Benjamin F. Cravatt

    (The Skaggs Institute for Chemical Biology, The Scripps Research Institute
    The Scripps Research Institute)

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.

Suggested Citation

  • Eranthie Weerapana & Chu Wang & Gabriel M. Simon & Florian Richter & Sagar Khare & Myles B. D. Dillon & Daniel A. Bachovchin & Kerri Mowen & David Baker & Benjamin F. Cravatt, 2010. "Quantitative reactivity profiling predicts functional cysteines in proteomes," Nature, Nature, vol. 468(7325), pages 790-795, December.
  • Handle: RePEc:nat:nature:v:468:y:2010:i:7325:d:10.1038_nature09472
    DOI: 10.1038/nature09472
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    Cited by:

    1. Yongjin Wang & Yang Zhou & Chaowei Shi & Jiacong Liu & Guohua Lv & Huisi Huang & Shengrong Li & Liping Duan & Xinyi Zheng & Yue Liu & Haibo Zhou & Yonghua Wang & Zhengqiu Li & Ke Ding & Pinghua Sun & , 2022. "A toxin-deformation dependent inhibition mechanism in the T7SS toxin-antitoxin system of Gram-positive bacteria," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Yan Xu & Jun Ding & Ling-Yun Wu, 2016. "iSulf-Cys: Prediction of S-sulfenylation Sites in Proteins with Physicochemical Properties of Amino Acids," PLOS ONE, Public Library of Science, vol. 11(4), pages 1-9, April.

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