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RZZ 复合物的结构及 Spindly 驱动的人染色体动粒冠状组装的分子基础。

Structure of the RZZ complex and molecular basis of Spindly-driven corona assembly at human kinetochores.

机构信息

Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany.

Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.

出版信息

EMBO J. 2022 May 2;41(9):e110411. doi: 10.15252/embj.2021110411. Epub 2022 Apr 4.

DOI:10.15252/embj.2021110411
PMID:35373361
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9058546/
Abstract

In metazoans, a ≈1 megadalton (MDa) multiprotein complex comprising the dynein-dynactin adaptor Spindly and the ROD-Zwilch-ZW10 (RZZ) complex is the building block of a fibrous biopolymer, the kinetochore fibrous corona. The corona assembles on mitotic kinetochores to promote microtubule capture and spindle assembly checkpoint (SAC) signaling. We report here a high-resolution cryo-EM structure that captures the essential features of the RZZ complex, including a farnesyl-binding site required for Spindly binding. Using a highly predictive in vitro assay, we demonstrate that the SAC kinase MPS1 is necessary and sufficient for corona assembly at supercritical concentrations of the RZZ-Spindly (RZZS) complex, and describe the molecular mechanism of phosphorylation-dependent filament nucleation. We identify several structural requirements for RZZS polymerization in rings and sheets. Finally, we identify determinants of kinetochore localization and corona assembly of Spindly. Our results describe a framework for the long-sought-for molecular basis of corona assembly on metazoan kinetochores.

摘要

在后生动物中，一种包含动力蛋白-动力素衔接蛋白 Spindly 和 ROD-Zwilch-ZW10 (RZZ) 复合物的约 1 兆道尔顿 (MDa) 多蛋白复合物是一种纤维状生物聚合物——动粒纤维冠状结构的构建模块。该冠状结构组装在有丝分裂动粒上，以促进微管捕获和纺锤体组装检查点 (SAC) 信号传导。我们在这里报告了一个高分辨率的冷冻电镜结构，该结构捕获了 RZZ 复合物的基本特征，包括 Spindly 结合所必需的法呢基结合位点。我们使用高度可预测的体外测定法证明，SAC 激酶 MPS1 对于在 RZZ-Spindly (RZZS) 复合物的超临界浓度下组装冠状结构是必需且充分的，并描述了磷酸化依赖性细丝成核的分子机制。我们确定了 RZZS 在环和片中聚合的几种结构要求。最后，我们确定了 Spindly 着丝粒定位和冠状结构组装的决定因素。我们的结果描述了后生动物动粒冠状结构组装的长期寻求的分子基础的框架。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/bd1e60678f8e/EMBJ-41-e110411-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/fdae5bfa1821/EMBJ-41-e110411-g013.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/ce9bd16cced6/EMBJ-41-e110411-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/81cd8a35cbcc/EMBJ-41-e110411-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/c3e235d5bfab/EMBJ-41-e110411-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/827726857835/EMBJ-41-e110411-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/02a94ae3b949/EMBJ-41-e110411-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/6e9d353dbb54/EMBJ-41-e110411-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/1287d3829fcc/EMBJ-41-e110411-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/bd1e60678f8e/EMBJ-41-e110411-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/fdae5bfa1821/EMBJ-41-e110411-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/1ca202208e59/EMBJ-41-e110411-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/54f4fdcdacfc/EMBJ-41-e110411-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/705d5478e657/EMBJ-41-e110411-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/ce9bd16cced6/EMBJ-41-e110411-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/81cd8a35cbcc/EMBJ-41-e110411-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/c3e235d5bfab/EMBJ-41-e110411-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/827726857835/EMBJ-41-e110411-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/02a94ae3b949/EMBJ-41-e110411-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/6e9d353dbb54/EMBJ-41-e110411-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/1287d3829fcc/EMBJ-41-e110411-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/034e/9058546/bd1e60678f8e/EMBJ-41-e110411-g005.jpg

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