Direct cysteine sulfenylation drives activation of the Src kinase

• DOI: 10.1038/s41467-018-06790-1
• Publication Date: 2018-10-24T15:05:30Z
• Authors: David E. Heppner; Christopher M. Du...; 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
• Keywords: Tyrosine-protein kinase CSK

Abstract The Src kinase controls aspects of cell biology and its activity is regulated by intramolecular structural changes induced protein interactions tyrosine phosphorylation. Recent studies indicate that additionally redox-dependent mechanisms, involving oxidative modification(s) cysteines within the protein, although nature molecular-level impact cysteine oxidation are unknown. Using a combination biochemical cell-based studies, we establish critical importance two residues, Cys-185 Cys-277, as targets for H 2 O -mediated sulfenylation (Cys-SOH) in activation response to NADPH oxidase-dependent signaling. Molecular dynamics metadynamics simulations reveal these cysteines, indicating Cys-277-SOH enables solvent exposure Tyr-416 promote (auto)phosphorylation, Cys-185-SOH destabilizes pTyr-527 binding SH2 domain. These mechanisms offer opportunities development Src-selective inhibitors treatment diseases where aberrantly activated.