The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein
The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein
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DOI：
10.1101/2022.04.13.488131
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发表时间：
2022-12
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影响因子：
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通讯作者：
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
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文献类型：
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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
在哺乳动物减数分裂前期，由细胞质动力蛋白驱动的染色体运动对于联会和遗传交换是必不可少的。动力蛋白通过KASH5和SUN1或SUN2连接到染色体端粒，它们一起跨越核膜。在这里，我们发现KASH5在体外促进动力蛋白的运动，而胞浆中的KASH5抑制动力蛋白的间期功能。KASH5通过LIC C末端的保守螺旋与动力蛋白轻中间链(DYNC1LI1或DYNC1LI2)相互作用，该区域也是动力蛋白募集到其他细胞膜所必需的。KASH5‘S N端EF-HAND是必不可少的，因为与动力蛋白的相互作用受到关键钙结合残基突变的干扰，尽管它不受细胞钙水平的调节。在KASH5-dynein复合体中，dynein可以独立于dynactin而被募集到KASH5的核膜上，而L is1则是dynactin掺入KASH5-dynein复合体所必需的。总之，我们证明了跨膜蛋白KASH5是动力蛋白的激活接头，并阐明了KASH5-动力蛋白-动力蛋白复合体的组装层次。
Cytoplasmic dynein-driven movement of chromosomes during prophase I of mammalian meiosis is essential for synapsis and genetic exchange. Dynein connects to chromosome telomeres via KASH5 and SUN1 or SUN2, which together span the nuclear envelope. Here, we show that KASH5 promotes dynein motility in vitro, and cytosolic KASH5 inhibits dynein’s interphase functions. KASH5 interacts with either dynein light intermediate chain (DYNC1LI1 or DYNC1LI2) via a conserved helix in the LIC C-terminal, and this region is also needed for dynein’s recruitment to other cellular membranes. KASH5’s N-terminal EF-hands are essential, as the interaction with dynein is disrupted by mutation of key calcium-binding residues, although it is not regulated by cellular calcium levels. Dynein can be recruited to KASH5 at the nuclear envelope independently of dynactin, while LIS1 is essential for dynactin incorporation into the KASH5-dynein complex. Altogether, we show that the trans-membrane protein KASH5 is an activating adaptor for dynein, and shed light on the hierarchy of assembly of KASH5-dynein-dynactin complexes.