Structural basis of protein kinase C isoform function.
Structural basis of protein kinase C isoform function.
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DOI：
10.1152/physrev.00034.2007
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发表时间：
2008-10
影响因子：
33.6
通讯作者：
Steinberg SF
中科院分区：
文献类型：
--
作者：
Steinberg SF
蛋白激酶C（PKC）亚型包括一个家族的脂质活化酶，涉及广泛的细胞功能。PKC是模块化酶，由调节结构域（其含有响应于脂质辅因子的膜靶向基序，并且在一些PKC钙的情况下）和结合ATP和底物的相对保守的催化结构域组成。这些酶在许多细胞类型中共表达并响应于类似的刺激激动剂。然而，有越来越多的证据表明，个别PKC亚型subserve独特的（在某些情况下，相反的）功能，在细胞中，至少部分是由于异构体特异性亚细胞区室化模式，蛋白质-蛋白质相互作用，和翻译后修饰，影响催化功能。本文综述了不同的脂质辅因子对单个PKC亚型的反应性的结构基础，调节磷酸化，控制正常的成熟，激活，信号功能，和下调这些酶，和内/分子间的相互作用，控制PKC亚型的激活和亚细胞靶向细胞。详细了解构成异构体特异性翻译后修饰模式、蛋白质-蛋白质相互作用和亚细胞靶向（即，赋予功能特异性）应该为设计新型PKC亚型特异性激活剂或抑制剂化合物提供基础，这些化合物可以实现细胞中PKC信号传导的治疗上有用的变化。
Protein kinase C (PKC) isoforms comprise a family of lipid-activated enzymes that have been implicated in a wide range of cellular functions. PKCs are modular enzymes comprised of a regulatory domain (that contains the membrane-targeting motifs that respond to lipid cofactors, and in the case of some PKCs calcium) and a relatively conserved catalytic domain that binds ATP and substrates. These enzymes are coexpressed and respond to similar stimulatory agonists in many cell types. However, there is growing evidence that individual PKC isoforms subserve unique (and in some cases opposing) functions in cells, at least in part as a result of isoform-specific subcellular compartmentalization patterns, protein-protein interactions, and posttranslational modifications that influence catalytic function. This review focuses on the structural basis for differences in lipid cofactor responsiveness for individual PKC isoforms, the regulatory phosphorylations that control the normal maturation, activation, signaling function, and downregulation of these enzymes, and the intra-/intermolecular interactions that control PKC isoform activation and subcellular targeting in cells. A detailed understanding of the unique molecular features that underlie isoform-specific posttranslational modification patterns, protein-protein interactions, and subcellular targeting (i.e., that impart functional specificity) should provide the basis for the design of novel PKC isoform-specific activator or inhibitor compounds that can achieve therapeutically useful changes in PKC signaling in cells.
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