Phosphorylation of CENP-C by Aurora B facilitates kinetochore attachment error correction in mitosis.
Phosphorylation of CENP-C by Aurora B facilitates kinetochore attachment error correction in mitosis.
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Aurora B 磷酸化 CENP-C 促进有丝分裂中着丝粒附着错误的纠正
DOI：
10.1073/pnas.1710506114
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发表时间：
2017-12-12
影响因子：
11.1
通讯作者：
Zang J
中科院分区：
文献类型：
--
作者：
Zhou X;Zheng F;Wang C;Wu M;Zhang X;Wang Q;Yao X;Fu C;Zhang X;Zang J
着丝粒是位于着丝粒上的大型蛋白质网络，在有丝分裂期间介导染色体分离并维持基因组稳定性。Mis 12复合物（Mis 12 C）通过与CENP-C缔合而充当将Ndc 80和Knl 1复合物靶向至着丝粒的支架。在这里，我们提供了深入了解的分子机制的CENP-C依赖的着丝粒募集Mis 12 C，这是负调控极光B依赖的CENP-C磷酸化。用磷酸化模拟突变体Cnp 3 T28 E替换粟酒裂殖酵母Cnp 3，导致由不适当的动粒组装引起的有缺陷的染色体分离。这些发现表明，极光B依赖性磷酸化CENP-C在中断内部和外部动粒之间的连接中起作用，因此参与错误校正/纺锤体组装检查点途径，以防止有丝分裂期间的染色体错误分离。着丝粒是一种超蛋白复合物，通过与纺锤体微管的动态相互作用协调染色体分离。CENP-C和Mis 12-Ndc 80-Knl 1（KMN）蛋白网络之间的物理连接是用于在CENP-A核小体上组装动粒的重要途径。多个外部动粒组分被Aurora B激酶磷酸化以激活纺锤体组装检查点（SAC）并确保准确的染色体分离。然而，Aurora B是否能磷酸化内部动粒组分以促进有丝分裂染色体的正确分离尚不清楚。在这里，我们报道了裂殖酵母裂殖酵母Mis 12-Nnf 1复合物的结构，并表明Cnp 3（S. pombe）负责与Mis 12复合体相互作用。有趣的是，Cnp 3的Thr 28是Ark 1（S. pombe），并且磷酸化损害Cnp 3和Mis 12复合物之间的相互作用。磷酸化模拟Cnp 3突变体的表达由于不正确的动粒组装导致有缺陷的染色体分离。这些结果建立了一个以前未表征的监管机制，参与CENP-C-Mis 12促进动粒附着错误校正，以确保在有丝分裂过程中准确的染色体分离。
Significance Kinetochores are large protein networks located on centromeres that mediate chromosome segregation during mitosis and maintain genomic stability. Mis12 complex (Mis12C) functions as a scaffold that targets Ndc80 and Knl1 complexes to the centromere by associating with CENP-C. Here, we provide insights into the molecular mechanism underlying the CENP-C–dependent kinetochore recruitment of Mis12C, which is negatively regulated by Aurora B-dependent CENP-C phosphorylation. Replacement of Schizosaccharomyces pombe Cnp3 with a phosphorylation-mimicking mutant, Cnp3T28E, results in defective chromosome segregation caused by improper kinetochore assembly. These findings indicate that Aurora B-dependent phosphorylation of CENP-C plays a role in interrupting the connection between the inner and outer kinetochore and is thus involved in the error correction/spindle assembly checkpoint pathway to prevent chromosome missegregation during mitosis. Kinetochores are superprotein complexes that orchestrate chromosome segregation via a dynamic interaction with spindle microtubules. A physical connection between CENP-C and the Mis12–Ndc80–Knl1 (KMN) protein network is an important pathway that is used to assemble kinetochores on CENP-A nucleosomes. Multiple outer kinetochore components are phosphorylated by Aurora B kinase to activate the spindle assembly checkpoint (SAC) and to ensure accurate chromosome segregation. However, it is unknown whether Aurora B can phosphorylate inner kinetochore components to facilitate proper mitotic chromosome segregation. Here, we reported the structure of the fission yeast Schizosaccharomyces pombe Mis12–Nnf1 complex and showed that N-terminal residues 26–50 in Cnp3 (the CENP-C homolog of S. pombe) are responsible for interacting with the Mis12 complex. Interestingly, Thr28 of Cnp3 is a substrate of Ark1 (the Aurora B homolog of S. pombe), and phosphorylation impairs the interaction between the Cnp3 and Mis12 complex. The expression of a phosphorylation-mimicking Cnp3 mutant results in defective chromosome segregation due to improper kinetochore assembly. These results establish a previously uncharacterized regulatory mechanism involved in CENP-C–Mis12-facilitated kinetochore attachment error correction to ensure accurate chromosome segregation during mitosis.
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DOI：
10.1038/nrm3494
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.3
作者：
Alexander J;Lim D;Joughin BA;Hegemann B;Hutchins JR;Ehrenberger T;Ivins F;Sessa F;Hudecz O;Nigg EA;Fry AM;Musacchio A;Stukenberg PT;Mechtler K;Peters JM;Smerdon SJ;Yaffe MB
通讯作者：
Yaffe MB
影响因子：
64.5
作者：
Chen, Zhongzhou;Zang, Jianye;Zhang, Gongyi
通讯作者：
Zhang, Gongyi
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.5
作者：
Ciferri, Claudio;Pasqualato, Sebastiano;Musacchio, Andrea
通讯作者：
Musacchio, Andrea