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研究揭示内部动粒CCAN复合物结构
2019-10-03 21:16

2019年10月2日《自然》杂志在线发表了英国科学家的一项最新研究成果。来自MRC分子生物学实验室的David Barford研究小组,解析了内部动粒CCAN复合物组装到着丝粒核小体上的结构。

研究人员报道了酿酒酵母内部动粒模块,即CCAN(constitutive centromere associated network)复合物组装到Cenp-A核小体上的冷冻电镜结构(CCAN-Cenp-ANuc)。该结构解释了CCAN组成亚复合物的相互依赖性,并显示了CCAN的Y形开口如何容纳Cenp-ANuc,以使特定的CCAN亚基能够接触核小体DNA和组蛋白亚基。在Cenp-ANuc的两个末端与未包裹的DNA双链体的相互作用主要由Cenp-L-Cenp-N亚复合体中的DNA结合槽介导。这些相互作用的破坏削弱了CCAN在Cenp-ANuc上的组装。

这些数据表明CCAN对Cenp-A核小体的识别机制,以及CCAN如何充当外部动粒组装平台,将着丝粒连接到有丝分裂纺锤体上进行染色体分离。

据介绍,在真核生物中,有丝分裂和减数分裂中准确的染色体分离可保持基因组稳定性并防止非整倍性。动粒是大蛋白复合物,通过组装到专门的Cenp-A核小体上,起到将着丝粒染色质连接到有丝分裂纺锤体微管的作用。脊椎动物染色体的着丝粒包含数百万个DNA碱基对并附着在多个微管上,而出芽酵母的简单点着丝粒则连接到单个微管上。16个出芽酵母染色体全都使用单个Cenp-A核小体(Cenp-ANuc)组装完整的动粒,每个核小体都完美地位于其同源着丝粒上。内部和外部动粒模块分别负责着丝粒染色质和微管的相互作用。

附:英文原文

Title: Structure of the inner kinetochore CCAN complex assembled onto a centromeric nucleosome

Author: Kaige Yan, Jing Yang, Ziguo Zhang, Stephen H. McLaughlin, Leifu Chang, Domenico Fasci, Ann E. Ehrenhofer-Murray, Albert J. R. Heck, David Barford

Issue&Volume: 2019-10-02

Abstract: 

In eukaryotes, accurate chromosome segregation in mitosis and meiosis maintains genome stability and prevents aneuploidy. Kinetochores are large protein complexes that, by assembling onto specialized Cenp-A nucleosomes1,2, function to connect centromeric chromatin to microtubules of the mitotic spindle3,4. Whereas the centromeres of vertebrate chromosomes comprise millions of DNA base pairs and attach to multiple microtubules, the simple point centromeres of budding yeast are connected to individual microtubules5,6. All 16 budding yeast chromosomes assemble complete kinetochores using a single Cenp-A nucleosome (Cenp-ANuc), each of which is perfectly centred on its cognate centromere7,8,9. The inner and outer kinetochore modules are responsible for interacting with centromeric chromatin and microtubules, respectively. Here we describe the cryo-electron microscopy structure of the Saccharomyces cerevisiae inner kinetochore module, the constitutive centromere associated network (CCAN) complex, assembled onto a Cenp-A nucleosome (CCAN–Cenp-ANuc). The structure explains the interdependency of the constituent subcomplexes of CCAN and shows how the Y-shaped opening of CCAN accommodates Cenp-ANuc to enable specific CCAN subunits to contact the nucleosomal DNA and histone subunits. Interactions with the unwrapped DNA duplex at the two termini of Cenp-ANuc are mediated predominantly by a DNA-binding groove in the Cenp-L–Cenp-N subcomplex. Disruption of these interactions impairs assembly of CCAN onto Cenp-ANuc. Our data indicate a mechanism of Cenp-A nucleosome recognition by CCAN and how CCAN acts as a platform for assembly of the outer kinetochore to link centromeres to the mitotic spindle for chromosome segregation.

DOI: 10.1038/s41586-019-1609-1

Source:https://www.nature.com/articles/s41586-019-1609-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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