Direct cysteine sulfenylation drives activation of the Src kinase

David E Heppner; Christopher M Dustin; Chenyi Liao; Milena Hristova; Carmen Veith; Andrew C Little; Bethany A Ahlers; Sheryl L White; Bin Deng; Ying-Wai Lam; Jianing Li; Albert van der Vliet

doi:10.1038/s41467-018-06790-1

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Direct cysteine sulfenylation drives activation of the Src kinase

Journal article

Open access

Peer reviewed

Direct cysteine sulfenylation drives activation of the Src kinase

David E Heppner, Christopher M Dustin, Chenyi Liao, Milena Hristova, Carmen Veith, Andrew C Little, Bethany A Ahlers, Sheryl L White, Bin Deng, Ying-Wai Lam, …

Nature communications, Vol.9(1), 4522

10/30/2018

DOI: 10.1038/s41467-018-06790-1

PMCID: PMC6207713

PMID: 30375386

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Abstract

The Src kinase controls aspects of cell biology and its activity is regulated by intramolecular structural changes induced by protein interactions and tyrosine phosphorylation. Recent studies indicate that Src is additionally regulated by redox-dependent mechanisms, involving oxidative modification(s) of cysteines within the Src protein, although the nature and molecular-level impact of Src cysteine oxidation are unknown. Using a combination of biochemical and cell-based studies, we establish the critical importance of two Src cysteine residues, Cys-185 and Cys-277, as targets for H O -mediated sulfenylation (Cys-SOH) in redox-dependent kinase activation in response to NADPH oxidase-dependent signaling. Molecular dynamics and metadynamics simulations reveal the structural impact of sulfenylation of these cysteines, indicating that Cys-277-SOH enables solvent exposure of Tyr-416 to promote its (auto)phosphorylation, and that Cys-185-SOH destabilizes pTyr-527 binding to the SH2 domain. These redox-dependent Src activation mechanisms offer opportunities for development of Src-selective inhibitors in treatment of diseases where Src is aberrantly activated.

Phosphorylation

Cell Line, Tumor

Cysteine - metabolism

Humans

Hydrogen Peroxide - metabolism

Molecular Dynamics Simulation

Oxidation-Reduction

Protein Binding

Protein Structure, Tertiary

Proto-Oncogene Proteins pp60(c-src) - metabolism

src Homology Domains

Details

Title: Subtitle: Direct cysteine sulfenylation drives activation of the Src kinase
Creators: David E Heppner - Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave, Boston, MA, 02115, USA. david_heppner@dfci.harvard.edu
Christopher M Dustin - Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine University of Vermont, 149 Beaumont Avenue, Burlington, VT, 05405, USA
Chenyi Liao - Department of Chemistry, College of Arts and Sciences, University of Vermont, 82 University Place, Burlington, VT, 05405, USA
Milena Hristova - Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine University of Vermont, 149 Beaumont Avenue, Burlington, VT, 05405, USA
Carmen Veith - Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine University of Vermont, 149 Beaumont Avenue, Burlington, VT, 05405, USA
Andrew C Little - Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine University of Vermont, 149 Beaumont Avenue, Burlington, VT, 05405, USA
Bethany A Ahlers - University of Iowa, Anatomy and Cell Biology
Sheryl L White - Department of Neurological Sciences, Robert Larner, M.D. College of Medicine University of Vermont, 149 Beaumont Avenue, Burlington, VT, 05405, USA
Bin Deng - Department of Biology, College of Arts and Sciences, University of Vermont, 109 Carrigan Drive, Burlington, VT, 05405, USA
Ying-Wai Lam - Department of Biology, College of Arts and Sciences, University of Vermont, 109 Carrigan Drive, Burlington, VT, 05405, USA
Jianing Li - Department of Chemistry, College of Arts and Sciences, University of Vermont, 82 University Place, Burlington, VT, 05405, USA. jianing.li@uvm.edu
Albert van der Vliet - Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine University of Vermont, 149 Beaumont Avenue, Burlington, VT, 05405, USA. albert.van-der-vliet@med.uvm.edu
Resource Type: Journal article
Publication Details: Nature communications, Vol.9(1), 4522
DOI: 10.1038/s41467-018-06790-1
PMID: 30375386
PMCID: PMC6207713
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: HL085646 / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) P20 GM103449 / NIGMS NIH HHS ES021476 / U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS) HL138708 / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01 HL085646 / NHLBI NIH HHS T32 HL076122 / NHLBI NIH HHS R01 HL138708 / NHLBI NIH HHS F31 HL142221 / NHLBI NIH HHS
Language: English
Date published: 10/30/2018
Academic Unit: Anatomy and Cell Biology; Cardiothoracic Surgery
Record Identifier: 9984131899502771

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