Lis1 activates dynein motility by modulating its pairing with dynactin
Lis1 activates dynein motility by modulating its pairing with dynactin
复制标题
DOI：
10.1038/s41556-020-0501-4
复制
发表时间：
2020-04-27
影响因子：
21.3
通讯作者：
Yildiz, Ahmet
中科院分区：
文献类型：
--
作者：
Elshenawy, Mohamed M.;Kusakci, Emre;Yildiz, Ahmet
Lis 1调节动力蛋白活性。由Markus、Reck-Peterson和Yildiz实验室进行的三项独立但互补的研究证实了Lis 1在调节细胞内动力蛋白的定位、活性和功能中的关键作用，Lis 1（Lissencephaly-1，Lis 1）是动力蛋白介导的细胞内微管负端转运的关键辅因子。目前还不清楚Lis 1是否作为哺乳动物动力蛋白运动的抑制剂或激活剂。在这里，我们使用单分子成像和光学捕获显示，Lis 1并不直接改变与dynactin和货物适配器组装的单个动力蛋白马达的步进和力的产生。相反，Lis 1促进与dynactin形成活性复合物。Lis 1还支持将两个动力蛋白添加到动力蛋白中，从而在拔河比赛中提高速度，产生更高的力，并与驱动蛋白进行更有效的竞争。Lis 1与能动复合物分离，表明其主要作用是协调运输机制的组装。我们建议，Lis 1结合释放动力蛋白从其自身抑制状态，这提供了一个机械解释，为什么Lis 1是必需的许多动力蛋白相关的货物在细胞中的有效运输。
Lis1 regulates dynein activity. Three independent but complementary studies by the laboratories of Markus, Reck-Peterson and Yildiz identify a key role for Lis1 in modulating localization, activity and function of dynein in cells.Lissencephaly-1 (Lis1) is a key cofactor for dynein-mediated intracellular transport towards the minus-ends of microtubules. It remains unclear whether Lis1 serves as an inhibitor or an activator of mammalian dynein motility. Here we use single-molecule imaging and optical trapping to show that Lis1 does not directly alter the stepping and force production of individual dynein motors assembled with dynactin and a cargo adaptor. Instead, Lis1 promotes the formation of an active complex with dynactin. Lis1 also favours the recruitment of two dyneins to dynactin, resulting in increased velocity, higher force production and more effective competition against kinesin in a tug-of-war. Lis1 dissociates from motile complexes, indicating that its primary role is to orchestrate the assembly of the transport machinery. We propose that Lis1 binding releases dynein from its autoinhibited state, which provides a mechanistic explanation for why Lis1 is required for efficient transport of many dynein-associated cargos in cells.