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 () and Albert Vliet ()
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David E. Heppner: Robert Larner, M.D. College of Medicine University of Vermont
Christopher M. Dustin: Robert Larner, M.D. College of Medicine University of Vermont
Chenyi Liao: College of Arts and Sciences, University of Vermont
Milena Hristova: Robert Larner, M.D. College of Medicine University of Vermont
Carmen Veith: Robert Larner, M.D. College of Medicine University of Vermont
Andrew C. Little: Robert Larner, M.D. College of Medicine University of Vermont
Bethany A. Ahlers: College of Arts and Sciences, University of Vermont
Sheryl L. White: Robert Larner, M.D. College of Medicine University of Vermont
Bin Deng: College of Arts and Sciences, University of Vermont
Ying-Wai Lam: College of Arts and Sciences, University of Vermont
Jianing Li: College of Arts and Sciences, University of Vermont
Albert Vliet: Robert Larner, M.D. College of Medicine University of Vermont

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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 H2O2-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.

Date: 2018
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DOI: 10.1038/s41467-018-06790-1

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