The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
J Cell Biol. 2021 Aug 2;220(8). doi: 10.1083/jcb.202007167. Epub 2021 Jun 17.
WDR62 is a microcephaly-related, microtubule (MT)-associated protein (MAP) that localizes to the spindle pole and regulates spindle organization, but the underlying mechanisms remain elusive. Here, we show that WDR62 regulates spindle dynamics by recruiting katanin to the spindle pole and further reveal a TPX2-Aurora A-WDR62-katanin axis in cells. By combining cellular and in vitro experiments, we demonstrate that WDR62 shows preference for curved segments of dynamic GDP-MTs, as well as GMPCPP- and paclitaxel-stabilized MTs, suggesting that it recognizes extended MT lattice. Consistent with this property, WDR62 alone is inefficient in recruiting katanin to GDP-MTs, while WDR62 complexed with TPX2/Aurora A can potently promote katanin-mediated severing of GDP-MTs in vitro. In addition, the MT-binding affinity of WDR62 is autoinhibited through JNK phosphorylation-induced intramolecular interaction. We propose that WDR62 is an atypical MAP and functions as an adaptor protein between its recruiting factor TPX2/Aurora A and the effector katanin to orchestrate the regulation of spindle dynamics.
WDR62 是一种与小头畸形相关的微管（MT）相关蛋白（MAP），它定位于纺锤体极并调节纺锤体的组织，但潜在的机制仍不清楚。在这里，我们表明 WDR62 通过招募katanin 到纺锤体极来调节纺锤体动力学，并进一步揭示了细胞中的 TPX2-Aurora A-WDR62-katanin 轴。通过结合细胞和体外实验，我们证明 WDR62 对 GDP-MTs 的动态弯曲段以及 GMPCPP 和紫杉醇稳定的 MT 具有偏好性，表明它识别延伸的 MT 晶格。与该特性一致，WDR62 本身在将 katanin 招募到 GDP-MTs 中效率不高，而与 TPX2/Aurora A 复合的 WDR62 可以在体外有力地促进 katanin 介导的 GDP-MTs 的切割。此外，WDR62 的 MT 结合亲和力通过 JNK 磷酸化诱导的分子内相互作用而被自动抑制。我们提出，WDR62 是一种非典型的 MAP，并作为其募集因子 TPX2/Aurora A 与其效应因子 katanin 之间的衔接蛋白，协调纺锤体动力学的调节。
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