The multifaceted allosteric regulation of Aurora kinase A.
The multifaceted allosteric regulation of Aurora kinase A.
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DOI：
10.1042/bcj20170771
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发表时间：
2018-06-26
期刊：
影响因子：
--
通讯作者：
Levinson NM
中科院分区：
文献类型：
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作者：
Levinson NM
在所有真核生物中，蛋白激酶极光A （AurA）对双极性有丝分裂纺锤体的形成至关重要。在纺锤体组装过程中，AurA通过中心体和纺锤体微管两种不同的途径被激活。最近的研究表明，这些途径在分子水平上的运作方式截然不同，通过激酶结构域的结构和动力学的多方面变化激活AurA。这些进展为蛋白激酶精细调节控制提供了一个亲密的原子水平视图，揭示了提供分级调节控制水平的变构协同作用机制，以及激活环上磷酸化的激酶激活机制。在这里，我回顾了我们对AurA功能的理解的这些进展，并讨论了它们对使用变构小分子抑制剂来解决最近发现的AurA在神经母细胞瘤、前列腺癌和黑色素瘤中的作用的影响。
The protein kinase Aurora A (AurA) is essential for the formation of bipolar mitotic spindles in all eukaryotic organisms. During spindle assembly, AurA is activated through two different pathways operating at centrosomes and on spindle microtubules. Recent studies have revealed that these pathways operate quite differently at the molecular level, activating AurA through multifaceted changes to the structure and dynamics of the kinase domain. These advances provide an intimate atomic-level view of the finely tuned regulatory control operating in protein kinases, revealing mechanisms of allosteric cooperativity that provide graded levels of regulatory control, and a previously unanticipated mechanism for kinase activation by phosphorylation on the activation loop. Here, I review these advances in our understanding of AurA function, and discuss their implications for the use of allosteric small molecule inhibitors to address recently discovered roles of AurA in neuroblastoma, prostate cancer and melanoma.