Spatial separation of phosphatase and kinase activity within the Bub complex is required for proper mitosis
作者机构：The Cancer InstituteThe Affiliated Hospital of Qingdao UniversityQingdao UniversityQingdao 266061China Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagen DK-2200Denmark The Department of Genetics and Cell BiologyBasic Medical CollegeQingdao UniversityQingdao 266061China Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China
出 版 物：《Journal of Molecular Cell Biology》 (分子细胞生物学报（英文版）)
年 卷 期：2022年第14卷第11期
页 面：24-35页
核心收录：
学科分类：0710[理学-生物学] 07[理学] 09[农学] 071007[理学-遗传学] 0901[农学-作物学] 090102[农学-作物遗传育种]
基 金：supported by the National Natural Science Foundation of China(31970666) Taishan Scholar Project(tsqn201812054)from Shandong,China Work at the Novo Nordisk Foundation Center for Protein Research was supported by the grant NNF14CC0001 J.N.is supported by grants from the Danish Cancer Society(R269-A15586-B17) Independent Research Fund Denmark(8021-00101B and 0134-00199B) Novo Nordisk Foundation(NNF20OC0065098)
主 题：mitosis spindle assembly checkpoint kinetochores Bub1 BubR1 PP2A/B56
摘 要：The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogs with Bub1 being a kinase, while BubR1 localizes the PP2A-B56 protein phosphatase to kinetochores in humans. Whether this spatial separation of kinase and phosphatase activity is important is unclear as some organisms integrate both activities into one Bub protein. Here, we engineer human Bub1 and BubR1 proteins integrating kinase and phosphatase activities into one protein and show that these do not support normal mitotic progression. A Bub1–PP2A-B56 complex can support chromosome alignment but results in impairment of the checkpoint due to dephosphorylation of the Mad1 binding site in Bub1. Furthermore, a chimeric BubR1 protein containing the Bub1 kinase domain induces delocalized H2ApT120 phosphorylation, resulting in the reduction of centromeric hSgo2 and chromosome segregation errors. Collectively, these results argue that the spatial separation of kinase and phosphatase activities within the Bub complex is required for balancing its functions in the checkpoint and chromosome alignment.
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