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.

中文翻译：

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Lis1通过调节动力蛋白与动力蛋白的配对激活动力蛋白。

Lissencephaly-1（Lis1）是动力蛋白介导的向微管负端的细胞内转运的关键辅助因子。尚不清楚Lis1是作为哺乳动物动力蛋白的抑制剂还是激活剂。在这里，我们使用单分子成像和光阱技术来证明Lis1不会直接改变与动力蛋白和货物适配器组装在一起的个别动力蛋白马达的步进和力产生。而是，Lis1促进与动力蛋白形成活性复合物。Lis1还赞成在动力蛋白上招募两个达因素，从而在拔河中提高速度，提高力量产生并更有效地与驱动蛋白竞争。Lis1与运动复合物分离，表明Lis1的主要作用是协调运输机械的组装。