Cyclin B1 scaffolds MAD1 at the kinetochore corona to activate the mitotic checkpoint
Cyclin B1 scaffolds MAD1 at the kinetochore corona to activate the mitotic checkpoint
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DOI：
10.15252/embj.2019103180
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发表时间：
2020-03-23
期刊：
影响因子：
11.4
通讯作者：
Saurin, Adrian T.
中科院分区：
文献类型：
--
作者：
Allan, Lindsey A.;Reis, Magda Camacho;Saurin, Adrian T.
细胞周期蛋白B：CDK 1是有丝分裂的主要激酶调节因子。我们在这里表明，除了它的激酶功能，哺乳动物细胞周期蛋白B也支架一个本地化的信号通路，以帮助保持基因组的稳定性。细胞周期蛋白B1定位于外动粒的扩展区域，称为冠状区，在那里它通过直接与MAD 1结合来支撑纺锤体组装检查点（SAC）机制。体外重组将关键的结合界面映射到MAD 1 N端区域的一些酸性残基上，该序列的点突变废除了MAD 1的冠状区定位并削弱了SAC。因此，细胞周期蛋白B1是长期以来寻找的将MAD 1连接到冠的支架，并且需要这种特定的MAD 1库来产生强大的SAC反应。由于细胞周期蛋白B1：MAD 1定位在冠状结构建立后失去了对MPS 1激酶的依赖性，从而确保了冠状结构定位的MAD 1在MPS 1活性较低时仍然可以被磷酸化，因此产生了鲁棒性。因此，这项研究解释了corona-MAD 1如何产生强大的SAC信号，并揭示了关键有丝分裂激酶Cyclin B1：CDK 1的支架作用，最终有助于抑制其自身的降解。
Cyclin B:CDK1 is the master kinase regulator of mitosis. We show here that, in addition to its kinase functions, mammalian Cyclin B also scaffolds a localised signalling pathway to help preserve genome stability. Cyclin B1 localises to an expanded region of the outer kinetochore, known as the corona, where it scaffolds the spindle assembly checkpoint (SAC) machinery by binding directly toMAD1.In vitroreconstitutions map the key binding interface to a few acidic residues in the N-terminal region ofMAD1, and point mutations in this sequence abolishMAD1 corona localisation and weaken theSAC. Therefore, Cyclin B1 is the long-sought-after scaffold that linksMAD1 to the corona, and this specific pool ofMAD1 is needed to generate a robustSACresponse. Robustness arises because Cyclin B1:MAD1 localisation loses dependence onMPS1 kinase after the corona has been established, ensuring that corona-localisedMAD1 can still be phosphorylated whenMPS1 activity is low. Therefore, this study explains how corona-MAD1 generates a robustSACsignal, and it reveals a scaffolding role for the key mitotic kinase, Cyclin B1:CDK1, which ultimately helps to inhibit its own degradation.