Conserved Roles for the Dynein Intermediate Chain and Ndel1 in Assembly and Activation of Dynein.
Conserved Roles for the Dynein Intermediate Chain and Ndel1 in Assembly and Activation of Dynein.
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动力蛋白中间链和 Ndel1 在动力蛋白组装和激活中的保守作用。
DOI：
10.1101/2023.01.13.523097
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
McKenney,RichardJ
中科院分区：
文献类型：
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作者：
Okada,Kyoko;Iyer,BharatR;Lammers,LindsayG;Gutierrez,Pedro;Li,Wenzhe;Markus,StevenM;McKenney,RichardJ
微管运动胞浆动力蛋白的过程性运输需要动力蛋白-动力蛋白-适配器复合体的调控组装。动力蛋白和动力蛋白之间的相互作用最初被认为是动力蛋白中间链N端和动力蛋白亚单位p150Glued的相互作用。然而，最近的低温电磁结构并没有解决这种相互作用，质疑其重要性。中间链还与与p150Glued竞争结合的NDE1/Ndel1相互作用。我们发现，中间链N-末端是一个关键的进化保守的枢纽，它与dynactin和Ndel1相互作用，后者招募Lis1来驱动复杂的组装。除了揭示中间链N-末端可能与p150Gluedin活性运输复合体结合外，我们的数据还支持一个模型，即Ndel1-Lis1必须在Lis1以时间离散的步骤移交给Dynein之前解离。我们的工作揭示了dynein激活途径中以前未知的步骤，并提供了对Lis1/Ndel1和dynactin/Cargo-Adapters整合活动的深入了解。
Processive transport by the microtubule motor cytoplasmic dynein requires the regulated assembly of a dynein-dynactin-adapter complex. Interactions between dynein and dynactin were initially ascribed to the dynein intermediate chain N-terminus and the dynactin subunit p150Glued. However, recent cryo-EM structures have not resolved this interaction, questioning its importance. The intermediate chain also interacts with Nde1/Ndel1, which compete with p150Gluedfor binding. We reveal that the intermediate chain N-terminus is a critical evolutionarily conserved hub that interacts with dynactin and Ndel1, the latter of which recruits LIS1 to drive complex assembly. In additon to revealing that the intermediate chain N-terminus is likely bound to p150Gluedin active transport complexes, our data support a model whereby Ndel1-LIS1 must dissociate prior to LIS1 being handed off to dynein in temporally discrete steps. Our work reveals previously unknown steps in the dynein activation pathway, and provide insight into the integrated activities of LIS1/Ndel1 and dynactin/cargo-adapters.