Structures of human dynein in complex with the lissencephaly 1 protein, LIS1.
Structures of human dynein in complex with the lissencephaly 1 protein, LIS1.
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DOI：
10.7554/elife.84302
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发表时间：
2023-01-24
期刊：
影响因子：
7.7
通讯作者：
Reck-Peterson, Samara L.
中科院分区：
文献类型：
--
作者：
Reimer, Janice M.;DeSantis, Morgan E.;Leschziner, Andres E.;Reck-Peterson, Samara L.
无脑畸形1蛋白，LIS 1，在1型无脑畸形中突变，是细胞质动力蛋白-1的关键调节因子。在分子水平上，目前的模型提出，LIS 1激活动力蛋白通过解除其自身抑制的形式。之前我们报道了与LIS 1的酵母同源物Pac 1结合的酵母动力蛋白的3.1 Å结构，这揭示了它们相互作用的细节（吉利斯等人，2022年）。基于这种结构，我们进行了突变，破坏了这些相互作用，并表明它们是动力蛋白在酵母体内功能所必需的。我们还使用我们的酵母动力蛋白-Pac 1结构设计人类动力蛋白的突变，以探测LIS 1在促进活性动力蛋白复合物组装中的作用。这些突变对动力蛋白激活的影响相对温和，表明酵母和人类之间动力蛋白和Pac 1/LIS 1相互作用的方式可能存在差异。在这里，我们报告冷冻电镜结构的人动力蛋白LIS 1复合物。我们的新结构揭示了酵母和人类系统之间的差异，提供了一个蓝图，以更准确地破坏人类动力蛋白-LIS 1相互作用，并在动力蛋白-LIS 1复合物的背景下，映射1型无脑畸形疾病突变，以及与皮质发育畸形/智力残疾相关的动力蛋白突变。
The lissencephaly 1 protein, LIS1, is mutated in type-1 lissencephaly and is a key regulator of cytoplasmic dynein-1. At a molecular level, current models propose that LIS1 activates dynein by relieving its autoinhibited form. Previously we reported a 3.1 Å structure of yeast dynein bound to Pac1, the yeast homologue of LIS1, which revealed the details of their interactions (Gillies et al., 2022). Based on this structure, we made mutations that disrupted these interactions and showed that they were required for dynein’s function in vivo in yeast. We also used our yeast dynein-Pac1 structure to design mutations in human dynein to probe the role of LIS1 in promoting the assembly of active dynein complexes. These mutations had relatively mild effects on dynein activation, suggesting that there may be differences in how dynein and Pac1/LIS1 interact between yeast and humans. Here, we report cryo-EM structures of human dynein-LIS1 complexes. Our new structures reveal the differences between the yeast and human systems, provide a blueprint to disrupt the human dynein-LIS1 interactions more accurately, and map type-1 lissencephaly disease mutations, as well as mutations in dynein linked to malformations of cortical development/intellectual disability, in the context of the dynein-LIS1 complex.