Cytoplasmic dynein and KASH5: partners in fertility

细胞质动力蛋白和 KASH5：生育的伙伴

• 批准号: BB/N006933/1
• 负责人: Viki Allan
• 金额: $ 48.56万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN006933%2F1
• 关键词: Cytoplasmic; dynein; KASH5; partners; fertility

The birth of a healthy baby is the culmination of many complex processes, the first of which is the production of normal egg and sperm. This needs a specialised type of cell division, called meiosis. In most cells in our body, we have two copies of each chromosome: one each from our mother and father. Early during the first meiotic cell division, the two copies pair up in a process called synapsis, and swap regions of their DNA to give new combinations of genes. Synapsis is made much more efficient by movement of the chromosomes after they become attached to the membrane that surrounds the chromosomes, the nuclear envelope (NE). Chromosome movement is driven by a tiny motor, dynein, that walks along protein tracks in the cell pulling cargo with it. Dynein is linked to the chromosomes in meiosis by a protein complex that spans the NE, which contains a protein called KASH5. Dynein at the NE is also needed right after fertilization, when it transports the nucleus of the egg towards the sperm nucleus to allow their DNA to mix before the first division of the embryo. It is not known yet how dynein binds to the NE in this situation, but we predict that KASH5 does this job too. In this project, we will analyse in depth the mechanism and regulation of the dynein-KASH5 interaction, and see if it is also needed for pronuclear migration. Dynein is a very complex protein that is made up of 6 different subunits. Our preliminary work strongly suggests that KASH5 binds to dynein's light intermediate chains (LICs). We will work out which parts of KASH5 bind to which bit of the LIC, and how this interaction is regulated during the cell cycle. Very recent work has shown that dynein is activated by forming a stable complex with two other protein components: dynactin, and one of several adaptor proteins. We think that KASH5 acts as an adaptor protein too. We also predict that the LICs play a crucial role in assembling these active dynein complexes. We will test those ideas here.

健康婴儿的诞生是许多复杂过程的顶点，其中首先是正常鸡蛋和精子的产生。这需要一种专门的细胞分裂类型，称为减数分裂。在我们体内的大多数细胞中，我们都有两个染色体的副本：每个染色体都来自我们的父亲和父亲。在第一个减数分裂细胞分裂的早期，这两份副本在称为Synapsis的过程中配对，并将其DNA区域交换以提供新的基因组合。突触通过染色体附着在围绕染色体的膜（NE）附着的膜上后，使突触更有效。染色体运动是由一个小电动机Dynein驱动的，该动力蛋白沿着蛋白质轨道沿着细胞拉动货物的蛋白质轨道行驶。动力蛋白与跨NE的蛋白质复合物与减数分裂中的染色体联系起来，该蛋白质复合物包含一种称为Kash5的蛋白质​​。当受精后，还需要在NE处处于NE处的动力蛋白，当它将卵的核转运到精子核以使其DNA在胚胎的第一次分裂之前混合。在这种情况下，Dynein如何与NE结合，但我们预计Kash5也可以完成这项工作。在该项目中，我们将深入分析Dynein-Kash5相互作用的机制和调节，并查看是否还需要进行前核迁移。 Dynein是一种非常复杂的蛋白质，由6种不同的亚基组成。我们的初步工作强烈表明KASH5与Dynein的轻中间链（LICS）结合。我们将确定KASH5的哪些部分与LIC的哪一位结合，以及在细胞周期中如何调节这种相互作用。最近的工作表明，通过与其他两个蛋白质成分形成稳定的复合物：dynactin和几种衔接蛋白之一，可以激活动力蛋白。我们认为KASH5也充当衔接蛋白。我们还预测，LIC在组装这些活性动力蛋白复合物中起着至关重要的作用。我们将在这里测试这些想法。

项目成果

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

• DOI: 10.1101/2022.04.13.488131
• 发表时间: 2022-12
• 期刊: The Journal of Cell Biology
• 作者: Kirsten E. L. Garner;A. Salter;C. K. Lau;M. Gurusaran;Cécile Villemant;Elizabeth P. Granger;G. McNee;P. Woodman;O. Davies;B. Burke;V. Allan

The flexibility and dynamics of the tubules in the endoplasmic reticulum.

• DOI: 10.1038/s41598-017-16570-4
• 发表时间: 2017-11-28
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Georgiades P;Allan VJ;Wright GD;Woodman PG;Udommai P;Chung MA;Waigh TA
• 通讯作者: Waigh TA

A human infertility-associated KASH5 variant promotes mitochondrial localization.

人类不育相关的 KASH5 变异促进线粒体定位。

• DOI: 10.1038/s41598-021-89439-2
• 发表时间: 2021-05-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bentebbal SA;Meqbel BR;Salter A;Allan V;Burke B;Horn HF
• 通讯作者: Horn HF