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首页> 外文期刊>Molecular and Cellular Biology >The C2 Domain and Altered ATP-Binding Loop Phosphorylation at Ser359 Mediate the Redox-Dependent Increase in Protein Kinase C-δ Activity
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The C2 Domain and Altered ATP-Binding Loop Phosphorylation at Ser359 Mediate the Redox-Dependent Increase in Protein Kinase C-δ Activity

机译：C2域和Ser359处的ATP结合环磷酸化改变介导蛋白激酶C-δ活性的氧化还原依赖性增加。

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摘要

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.
机译：蛋白激酶C-δ（PKCδ）在细胞生长，存活和损伤中的不同作用已归因于PKCδ信号响应中的刺激特异性差异。 PKCδ在激动剂刺激的磷酸肌醇水解中激活的细胞中发挥膜定界作用。 PKCδ作为一种Tyr 313 -磷酸化酶从膜中释放出来，该酶在氧化应激过程中表现出高水平的脂质非依赖性活性并改变了底物特异性。本研究确定了PKCδ的Tyr 313 磷酸化铰链区与其磷酸酪氨酸结合的C2结构域之间的相互作用，该结构域通过减少Ser 359 <处的激酶结构域ATP定位环中的磷酸化间接控制PKCδ的酶学。 / sup>。我们发现野生型（WT）PKCδ当在Ser 359上具有磷酸模拟或大体积取代基时，对在活性位点具有丝氨酸作为磷酸受体残基的底物表现出强烈的偏好。相比之下，PKCδ-S359A对丝氨酸或苏氨酸作为磷酸受体残基的底物具有非脂质依赖性活性。心肌细胞的其他研究表明，氧化应激会降低天然PKCδ上Ser 359 的磷酸化，而PKCδ-S359A过表达会增加具有磷酸受体位点丝氨酸和苏氨酸残基的底物的磷酸化基础水平。总的来说，这些研究确定了一个控制ATP定位环磷酸化的C2结构域-pTyr 313 对接相互作用，它是PKCδ催化活性的一种新颖，动态调节且与生理相关的结构决定因素。

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