Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, South Korea.
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea.
Sci Adv. 2023 Apr 21;9(16):eadf8582. doi: 10.1126/sciadv.adf8582.
Aurora kinase A (AURKA) performs critical functions in mitosis. Thus, the activity and subcellular localization of AURKA are tightly regulated and depend on diverse factors including interactions with the multiple binding cofactors. How these different cofactors regulate AURKA to elicit different levels of activity at distinct subcellular locations and times is poorly understood. Here, we identified a conserved region of CEP192, the major cofactor of AURKA, that mediates the interaction with AURKA. Quantitative binding studies were performed to map the interactions of a conserved helix (Helix-1) within CEP192. The crystal structure of Helix-1 bound to AURKA revealed a distinct binding site that is different from other cofactor proteins such as TPX2. Inhibiting the interaction between Helix-1 and AURKA in cells led to the mitotic defects, demonstrating the importance of the interaction. Collectively, we revealed a structural basis for the CEP192-mediated AURKA regulation at the centrosome, which is distinct from TPX2-mediated regulation on the spindle microtubule.
极光激酶 A（AURKA）在有丝分裂中发挥关键作用。因此，AURKA 的活性和亚细胞定位受到严格调控，依赖于多种因素，包括与多个结合辅助因子的相互作用。这些不同的辅助因子如何调节 AURKA，在不同的亚细胞位置和时间产生不同水平的活性，目前还知之甚少。在这里，我们鉴定了 AURKA 的主要辅助因子 CEP192 的一个保守区域，该区域介导与 AURKA 的相互作用。进行了定量结合研究以绘制 CEP192 内的一个保守螺旋（Helix-1）的相互作用图。与 AURKA 结合的 Helix-1 的晶体结构揭示了一个独特的结合位点，与其他辅助因子蛋白（如 TPX2）不同。在细胞中抑制 Helix-1 和 AURKA 之间的相互作用导致有丝分裂缺陷，证明了相互作用的重要性。总的来说，我们揭示了 CEP192 在中心体介导的 AURKA 调节的结构基础，这与 TPX2 在纺锤体微管上介导的调节不同。
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