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Aromatic thiol-mediated cleavage of N–O bonds enables chemical ubiquitylation of folded proteins

Author

Listed:
  • Caroline E. Weller

    (University of Washington)

  • Abhinav Dhall

    (University of Washington)

  • Feizhi Ding

    (University of Washington)

  • Edlaine Linares

    (Instituto de Química-Universidade de São Paulo)

  • Samuel D. Whedon

    (University of Washington)

  • Nicholas A. Senger

    (University of Washington)

  • Elizabeth L. Tyson

    (University of Washington)

  • John D. Bagert

    (Princeton University)

  • Xiaosong Li

    (University of Washington)

  • Ohara Augusto

    (Instituto de Química-Universidade de São Paulo)

  • Champak Chatterjee

    (University of Washington)

Abstract

Access to protein substrates homogenously modified by ubiquitin (Ub) is critical for biophysical and biochemical investigations aimed at deconvoluting the myriad biological roles for Ub. Current chemical strategies for protein ubiquitylation, however, employ temporary ligation auxiliaries that are removed under harsh denaturing conditions and have limited applicability. We report an unprecedented aromatic thiol-mediated N–O bond cleavage and its application towards native chemical ubiquitylation with the ligation auxiliary 2-aminooxyethanethiol. Our interrogation of the reaction mechanism suggests a disulfide radical anion as the active species capable of cleaving the N–O bond. The successful semisynthesis of full-length histone H2B modified by the small ubiquitin-like modifier-3 (SUMO-3) protein further demonstrates the generalizability and compatibility of our strategy with folded proteins.

Suggested Citation

  • Caroline E. Weller & Abhinav Dhall & Feizhi Ding & Edlaine Linares & Samuel D. Whedon & Nicholas A. Senger & Elizabeth L. Tyson & John D. Bagert & Xiaosong Li & Ohara Augusto & Champak Chatterjee, 2016. "Aromatic thiol-mediated cleavage of N–O bonds enables chemical ubiquitylation of folded proteins," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12979
    DOI: 10.1038/ncomms12979
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