KIF2C condensation concentrates PLK1 and phosphorylated BRCA2 on kinetochore microtubules in mitosis.

IF 16.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Anastasiia Skobelkina, Manon Julien, Sylvain Jeannin, Simona Miron, Tom Egger, Rady Chaaban, Guillaume Bouvignies, Emile Alghoul, Rania Ghouil, Claire Friel, Didier Busso, Juan C Cañas, François-Xavier Theillet, Romain Le Bars, Aura Carreira, Angelos Constantinou, Jihane Basbous, Sophie Zinn-Justin
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Abstract

During mitosis, the microtubule depolymerase KIF2C, the tumor suppressor BRCA2, and the kinase PLK1 contribute to the control of kinetochore-microtubule attachments. Both KIF2C and BRCA2 are phosphorylated by PLK1, and BRCA2 phosphorylated at T207 (BRCA2-pT207) serves as a docking site for PLK1. Reducing this interaction results in unstable microtubule-kinetochore attachments. Here we identified that KIF2C also directly interacts with BRCA2-pT207. Indeed, the N-terminal domain of KIF2C adopts a Tudor/PWWP/MBT fold that unexpectedly binds to phosphorylated motifs. Using an optogenetic platform, we found that KIF2C forms membrane-less organelles that assemble through interactions mediated by this phospho-binding domain. KIF2C condensation does not depend on BRCA2-pT207 but requires active Aurora B and PLK1 kinases. Moreover, it concentrates PLK1 and BRCA2-pT207 in an Aurora B-dependent manner. Finally, KIF2C depolymerase activity promotes the formation of KIF2C condensates, but strikingly, KIF2C condensates exclude tubulin: they are located on microtubules, especially at their extremities. Altogether, our results suggest that, during the attachment of kinetochores to microtubules, the assembly of KIF2C condensates amplifies PLK1 and KIF2C catalytic activities and spatially concentrates BRCA2-pT207 at the extremities of microtubules. We propose that this novel and highly regulated mechanism contributes to the control of microtubule-kinetochore attachments, chromosome alignment, and stability.

在有丝分裂中,KIF2C缩合将PLK1和磷酸化的BRCA2集中在着丝点微管上。
在有丝分裂过程中,微管解聚合酶KIF2C、肿瘤抑制因子BRCA2和激酶PLK1有助于控制着丝点-微管附着。KIF2C和BRCA2都被PLK1磷酸化,而BRCA2在T207位点磷酸化(BRCA2- pt207)作为PLK1的对接位点。减少这种相互作用会导致微管-着丝点附着不稳定。这里我们发现KIF2C也直接与BRCA2-pT207相互作用。事实上,KIF2C的n端结构域采用Tudor/PWWP/MBT折叠,意想不到地结合磷酸化的基序。利用光遗传学平台,我们发现KIF2C形成无膜细胞器,通过磷酸化结合域介导的相互作用进行组装。KIF2C缩合不依赖于BRCA2-pT207,但需要活跃的Aurora B和PLK1激酶。此外,它以依赖Aurora b的方式浓缩PLK1和BRCA2-pT207。最后,KIF2C解聚合酶的活性促进了KIF2C凝聚物的形成,但引人注目的是,KIF2C凝聚物排除了微管蛋白:它们位于微管上,尤其是在微管的末端。总之,我们的研究结果表明,在着丝点附着到微管上的过程中,KIF2C凝聚物的组装放大了PLK1和KIF2C的催化活性,并在空间上将BRCA2-pT207集中在微管的末端。我们认为这种新的高度调控的机制有助于控制微管-着丝点附着、染色体排列和稳定性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Nucleic Acids Research
Nucleic Acids Research 生物-生化与分子生物学
CiteScore
27.10
自引率
4.70%
发文量
1057
审稿时长
2 months
期刊介绍: Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.
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