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

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 () and Champak Chatterjee ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12979

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