Kendrick Agnieszka A, Nguyen Kendrick H V, Ma Wen, Karasmanis Eva P, Amaro Rommie E, Reck-Peterson Samara L, Leschziner Andres E
Salk Institute for Biological Studies, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Nat Struct Mol Biol. 2025 May 23. doi: 10.1038/s41594-025-01558-w.
Cytoplasmic dynein-1 (dynein) is an essential molecular motor controlled in part by autoinhibition. Lis1, a key dynein regulator mutated in the neurodevelopmental disease lissencephaly, plays a role in dynein activation. We recently identified a structure of partially autoinhibited dynein bound to Lis1, which suggests an intermediate state in dynein's activation pathway. However, other structural information is needed to fully understand how Lis1 activates dynein. Here, we used cryo-EM and yeast dynein and Lis1 incubated with ATP at different time points to reveal conformations that we propose represent additional intermediate states in dynein's activation pathway. We solved 16 high-resolution structures, including 7 distinct dynein and dynein-Lis1 structures from the same sample. Our data support a model in which Lis1 relieves dynein autoinhibition by increasing its basal ATP hydrolysis rate and promoting conformations compatible with complex assembly and motility. Together, this analysis advances our understanding of dynein activation and the contribution of Lis1 to this process.
胞质动力蛋白-1（动力蛋白）是一种重要的分子马达，其部分受自身抑制作用调控。Lis1是在神经发育疾病无脑回畸形中发生突变的关键动力蛋白调节因子，在动力蛋白激活过程中发挥作用。我们最近鉴定出了与Lis1结合的部分自身抑制状态的动力蛋白结构，这表明了动力蛋白激活途径中的一种中间状态。然而，需要其他结构信息来全面了解Lis1如何激活动力蛋白。在这里，我们使用冷冻电镜以及在不同时间点与ATP孵育的酵母动力蛋白和Lis1，以揭示我们认为代表动力蛋白激活途径中其他中间状态的构象。我们解析了16个高分辨率结构，包括来自同一样品的7种不同的动力蛋白和动力蛋白-Lis1结构。我们的数据支持这样一种模型，即Lis1通过提高其基础ATP水解速率并促进与复合物组装和运动相容的构象来解除动力蛋白的自身抑制。总之，这一分析推进了我们对动力蛋白激活以及Lis1在此过程中的作用的理解。
