The C2 domain and altered ATP-binding loop phosphorylation at Ser359 mediate the redox-dependent increase in protein kinase C-δ activity

Jianli Gong, Yongneng Yao, Pingbo Zhang, Barath Udayasuryan, Elena V. Komissarova, Ju Chen, Sivaraj Sivaramakrishnan, Jennifer E. Van Eyk, Susan F. Steinberg

Research output: Contribution to journalArticle

Abstract

The diverse roles of protein kinase C-δ (PKCδ) in cellular growth, survival, and injury have been attributed to stimulus-specific differences in PKCδ signaling responses. PKCδ exerts membrane-delimited actions in cells activated by agonists that stimulate phosphoinositide hydrolysis. PKCδ is released from membranes as a Tyr313-phosphorylated enzyme that displays a high level of lipid-independent activity and altered substrate specificity during oxidative stress. This study identifies an interaction between PKCδ's Tyr313-phosphorylated hinge region and its phosphotyrosine-binding C2 domain that controls PKCδ's enzymology indirectly by decreasing phosphorylation in the kinase domain ATP-positioning loop at Ser359. We show that wild-type (WT) PKCδ displays a strong preference for substrates with serine as the phosphoacceptor residue at the active site when it harbors phosphomimetic or bulky substitutions at Ser359. In contrast, PKCδ-S359A displays lipid-independent activity toward substrates with either a serine or threonine as the phosphoacceptor residue. Additional studies in cardiomyocytes show that oxidative stress decreases Ser359 phosphorylation on native PKCδ and that PKCδ-S359A overexpression increases basal levels of phosphorylation on substrates with both phosphoacceptor site serine and threonine residues. Collectively, these studies identify a C2 domain pTyr313 docking interaction that controls ATP-positioning loop phosphorylation as a novel, dynamically regulated, and physiologically relevant structural determinant of PKCδ catalytic activity.

Original languageEnglish (US)
Pages (from-to)1727-1740
Number of pages14
JournalMolecular and Cellular Biology
Volume35
Issue number10
DOIs
StatePublished - 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Medicine(all)

Cite this

Gong, J., Yao, Y., Zhang, P., Udayasuryan, B., Komissarova, E. V., Chen, J., Sivaramakrishnan, S., Van Eyk, J. E., & Steinberg, S. F. (2015). The C2 domain and altered ATP-binding loop phosphorylation at Ser359 mediate the redox-dependent increase in protein kinase C-δ activity. Molecular and Cellular Biology, 35(10), 1727-1740. https://doi.org/10.1128/MCB.01436-14