An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells

Ekaterina V. Vinogradova*, Xiaoyu Zhang, David Remillard, Daniel C. Lazar, Radu M. Suciu, Yujia Wang, Giulia Bianco, Yu Yamashita, Vincent M. Crowley, Michael A. Schafroth, Minoru Yokoyama, David B. Konrad, Kenneth M. Lum, Gabriel M. Simon, Esther K. Kemper, Michael R. Lazear, Sifei Yin, Megan M. Blewett, Melissa M. Dix, Nhan NguyenMaxim N. Shokhirev, Emily N. Chin, Luke L. Lairson, Bruno Melillo, Stuart L. Schreiber, Stefano Forli, John R. Teijaro, Benjamin F. Cravatt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3,000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.

Original languageEnglish (US)
Pages (from-to)1009-1026.e29
JournalCell
Volume182
Issue number4
DOIs
StatePublished - Aug 20 2020
Externally publishedYes

Keywords

  • activity-based protein profiling
  • BIRC3
  • chemical proteomics
  • covalent
  • cysteine
  • electrophiles
  • human
  • ITK
  • protein degradation
  • T cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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