The regulation of protein phosphorylation
The regulation of protein phosphorylation
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DOI：
10.1042/bst0370627
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发表时间：
2009-08-01
影响因子：
3.9
通讯作者：
Johnson, Louise N.
中科院分区：
文献类型：
--
作者：
Johnson, Louise N.
磷酸化在细胞生命的几乎每个方面都起着至关重要的作用。蛋白激酶调节信号通路和细胞过程，其介导代谢、转录、细胞周期进程、分化、细胞骨架排列和细胞运动、凋亡、细胞间通讯以及神经元和免疫功能。蛋白激酶共有一个保守的催化结构域，其催化ATP的γ-磷酸转移到蛋白底物中的丝氨酸、苏氨酸或酪氨酸残基。激酶可以以活性或非活性状态存在，其由不同激酶中的多种机制调节，所述机制包括通过磷酸化的控制、通过可靶向其它分子的其它结构域的调节、通过其它亚基的结合和调节以及通过蛋白质-蛋白质缔合的控制。这篇诺华奖章演讲是在庆祝查尔斯达尔文诞辰200周年的蛋白质进化会议上发表的。我开始总结目前的意见，从蛋白质序列的激酶基因。然后，我回顾了蛋白质磷酸化的结构后果，使用我们的工作糖原磷酸化酶，以说明磷酸化的更戏剧性的后果之一。蛋白质磷酸化的调节在疾病状态下经常被破坏，蛋白激酶已成为药物开发的重要靶点。最后，我认为蛋白激酶作为药物靶点的最新进展，并描述了我们最近的一些工作与CDK 9（细胞周期蛋白依赖性激酶9）-细胞周期蛋白T，转录调节。
Phosphorylation plays essential roles in nearly every aspect of cell life. Protein kinases regulate signalling pathways and cellular processes that mediate metabolism, transcription, cell-cycle progression, differentiation, cytoskeleton arrangement and cell movement, apoptosis, intercellular communication, and neuronal and immunological functions. Protein kinases share a conserved catalytic domain, which catalyses the transfer of the gamma-phosphate of ATP to a serine, threonine or tyiosine residue in protein substrates. The kinase can exist in an active or inactive state regulated by a variety of mechanisms in different kinases that include control by phosphorylation, regulation by additional domains that may target other molecules, binding and regulation by additional subunits, and control by protein-protein association. This Novartis Medal Lecture Was delivered at a meeting on protein evolution celebrating the 200th anniversary of Charles Darwin's birth. I begin with a summary of current observations from protein sequences of kinase phylogeny. I then review the structural consequences of protein phosphorylation using our work on glycogen phosphorylase to illustrate one of the more dramatic consequences of phosphorylation. Regulation of protein phosphorylation is frequently disrupted in the diseased state, and protein kinases have become high-profile targets for drug development. Finally, I consider recent advances on protein kinases as drug targets and describe some of our recent work with CDK9 (cyclin-dependent kinase 9)-cyclin T, a regulator of transcription.