puc-header

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

66 Pages Posted: 30 Oct 2019 Sneak Peek Status: Review Complete

See all articles by Ekaterina Vinogradova

Ekaterina Vinogradova

The Scripps Research Institute - Department of Chemistry

Daniel Lazar

Pondicherry University - School of Management

Radu M. Suciu

The Scripps Research Institute - Department of Chemistry

Yujia Wang

The Scripps Research Institute - Department of Chemistry

Giulia Bianco

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Yu Yamashita

The Scripps Research Institute - Department of Chemistry

Vincent M. Crowley

The Scripps Research Institute - Department of Chemistry

Dave Remillard

The Scripps Research Institute - Department of Chemistry

Kenneth M. Lum

The Scripps Research Institute - Department of Chemistry

Gabriel M. Simon

Vividion Therapeutics

Esther K. Kemper

The Scripps Research Institute - Department of Chemistry

Michael R. Lazear

The Scripps Research Institute - Department of Chemistry

Sifei Yin

The Scripps Research Institute - Department of Chemistry

Megan M. Blewett

The Scripps Research Institute - Department of Chemistry

Melissa M. Dix

The Scripps Research Institute - Department of Chemistry

Nhan Nguyen

The Scripps Research Institute - Department of Immunology and Infectious Disease

Maxim Shokhirev

Salk Institute for Biological Studies - Integrative Genomics and Bioinformatics Core

Emily Chin

The Scripps Research Institute - Department of Chemistry

Luke Lairson

The Scripps Research Institute - Department of Chemistry

Stefano Forli

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

John R. Teijaro

The Scripps Research Institute - Department of Immunology and Infectious Disease

Benjamin F. Cravatt

The Scripps Research Institute - Department of Chemistry

More...

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 3000 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 direct functional perturbation and/or ligand-induced degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells, underscoring the potential of electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.

Suggested Citation

Vinogradova, Ekaterina and Lazar, Daniel and Suciu, Radu M. and Wang, Yujia and Bianco, Giulia and Yamashita, Yu and Crowley, Vincent M. and Remillard, Dave and Lum, Kenneth M. and Simon, Gabriel M. and Kemper, Esther K. and Lazear, Michael R. and Yin, Sifei and Blewett, Megan M. and Dix, Melissa M. and Nguyen, Nhan and Shokhirev, Maxim and Chin, Emily and Lairson, Luke and Forli, Stefano and Teijaro, John R. and Cravatt, Benjamin F., An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human Immune Cells (October 28, 2019). CELL-D-19-03016. Available at SSRN: https://ssrn.com/abstract=3476689
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Ekaterina Vinogradova

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Daniel Lazar

Pondicherry University - School of Management ( email )

Pondicherry, 605 014
India
+91-413-2654369 (Phone)

HOME PAGE: http://www.lazar.in

Radu M. Suciu

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Yujia Wang

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Giulia Bianco

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Yu Yamashita

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Vincent M. Crowley

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Dave Remillard

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Kenneth M. Lum

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Gabriel M. Simon

Vividion Therapeutics

5820 Nancy Ridge Dr
San Diego, CA 92121
United States

Esther K. Kemper

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Michael R. Lazear

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Sifei Yin

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Megan M. Blewett

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Melissa M. Dix

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Nhan Nguyen

The Scripps Research Institute - Department of Immunology and Infectious Disease

La Jolla, CA 92037
United States

Maxim Shokhirev

Salk Institute for Biological Studies - Integrative Genomics and Bioinformatics Core

10010 North Torrey Pines Road
La Jolla, CA 92037
United States

Emily Chin

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Luke Lairson

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Stefano Forli

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

John R. Teijaro

The Scripps Research Institute - Department of Immunology and Infectious Disease

La Jolla, CA 92037
United States

Benjamin F. Cravatt (Contact Author)

The Scripps Research Institute - Department of Chemistry

La Jolla, CA 92037
United States

Click here to go to Cell.com

Paper statistics

Abstract Views
292
Downloads
20