Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements.
Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements.
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DOI：
10.1038/nsmb.3391
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发表时间：
2017-05
影响因子：
16.8
通讯作者：
Roberts AJ
中科院分区：
文献类型：
--
作者：
Toropova K;Mladenov M;Roberts AJ
纤毛是一种多功能的细胞器，由绒毛内运输（IFT）的货物到纤毛的尖端。人们普遍认为，必须控制逆行IFT电机dynein-2，以便到达纤毛尖端，然后释放以为回程提供动力。然而，其机制尚不清楚。在这里，我们系统地将人体动力蛋白-2马达的机械化学定义为单体、二聚体和带有动力蛋白- ii的多马达组件。将这些数据与单粒子电子显微镜的见解相结合，我们发现动力蛋白-2二聚体本质上是自抑制的。抑制是通过捕获dynein-2的机械“连接体”和“柄”域在一个新的电机-电机界面中介导的。我们发现连接体介导的抑制使动力蛋白-2在体外通过动力蛋白- ii有效运输。这些结果表明二聚体动力蛋白之间存在一种保守的自动调节机制，该机制被利用为动力蛋白-2在IFT期间循环活动的开关。
Cilia are multi-functional organelles that are constructed using intraflagellar transport (IFT) of cargo to and from their tip. It is widely held that the retrograde IFT motor, dynein-2, must be controlled in order to reach the ciliary tip and then unleashed to power the return journey. However, the mechanism is unknown. Here, we systematically define the mechanochemistry of human dynein-2 motors as monomers, dimers, and multi-motor assemblies with kinesin-II. Combining these data with insights from single-particle electron microscopy, we discover that dynein-2 dimers are intrinsically autoinhibited. Inhibition is mediated by trapping dynein-2’s mechanical “linker” and “stalk” domains within a novel motor-motor interface. We find that linker-mediated inhibition enables efficient transport of dynein-2 by kinesin-II in vitro. These results suggest a conserved mechanism for autoregulation among dimeric dyneins, which is exploited as a switch for dynein-2’s recycling activity during IFT.