Dynein activation in vivo is regulated by the nucleotide states of its AAA3 domain.
Dynein activation in vivo is regulated by the nucleotide states of its AAA3 domain.
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DOI：
10.1016/j.cub.2021.07.081
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发表时间：
2021-10-25
期刊：
影响因子：
--
通讯作者：
Xiang X
中科院分区：
文献类型：
--
作者：
Qiu R;Zhang J;Rotty JD;Xiang X
细胞质动力蛋白由动力蛋白复合物、货物衔接子和LIS 1（无脑畸形1）激活。这一过程在体内是如何调节的尚不清楚。动力蛋白马达环包含六个AAA+（与多种细胞活动相关的ATP酶）结构域。在这里，我们使用的丝状真菌构巢曲霉研究是否ATP水解AAA 3调节动力蛋白激活的背景下，其他监管机构。在真菌菌丝中，早期内体经历动力蛋白介导的运动远离微管加上靠近菌丝尖端的末端。动力蛋白通常聚集在微管正末端。早期的内体衔接钩蛋白，与动力蛋白一起，驱动动力蛋白活化，使其重新定位到微管负端。这一激活过程依赖于LIS 1，但LIS 1在激活后倾向于与动力蛋白解离。在这项研究中，我们发现含有AAA 3处阻断ATP水解的突变的动力蛋白可以进行LIS 1非依赖性激活，这与我们的遗传数据一致，即相同的突变抑制了A. nidulans LIS 1缺失突变体。我们的数据还表明，阻断AAA 3 ATP水解可以在没有早期内体衔接子的情况下通过动力肌动蛋白激活动力蛋白。因此，动力蛋白积聚在微管负端，而早期内体停留在正端附近。在AAA 3处含有阻断ATP结合的突变的动力蛋白在很大程度上依赖于LIS 1的活化，但该突变异常地阻止了动力蛋白活化后的LIS 1解离。总之，我们的数据表明，AAA 3 ATP酶循环调节动力蛋白激活和货物结合之间的协调，以及动态动力蛋白-LIS 1相互作用。Qiu等人将细胞质动力蛋白AAA 3结构域的ATP酶循环与真菌细胞中动力蛋白的空间调节联系起来。具体而言，AAA 3 ATP酶循环允许动力蛋白在被货物衔接子、动力肌动蛋白和LIS 1激活之前在微管正端积累;它还允许LIS 1在其激活后从动力蛋白解离。
Cytoplasmic dynein is activated by the dynactin complex, cargo adapters and LIS1 (Lissencephaly 1). How this process is regulated in vivo remains unclear. The dynein motor ring contains six AAA+ (ATPases Associated with diverse cellular Activities) domains. Here we used the filamentous fungus Aspergillus nidulans to examine whether ATP hydrolysis at AAA3 regulates dynein activation in the context of other regulators. In fungal hyphae, early endosomes undergo dynein-mediated movement away from the microtubule plus ends near the hyphal tip. Dynein normally accumulates at the microtubule plus ends. The early endosomal adapter Hook protein, together with dynactin, drives dynein activation to cause its relocation to the microtubule minus ends. This activation process depends on LIS1, but LIS1 tends to dissociate from dynein after its activation. In this study, we found that dynein containing a mutation blocking ATP hydrolysis at AAA3 can undergo LIS1-independent activation, consistent with our genetic data that the same mutation suppresses the growth defect of the A. nidulans LIS1-deletion mutant. Our data also suggest that blocking AAA3 ATP hydrolysis allows dynein activation by dynactin without the early endosomal adapter. As a consequence, dynein accumulates at microtubule minus ends while early endosomes stay near the plus ends. Dynein containing a mutation blocking ATP binding at AAA3 largely depends on LIS1 for activation, but this mutation abnormally prevents LIS1 dissociation upon dynein activation. Together, our data suggest that the AAA3 ATPase cycle regulates the coordination between dynein activation and cargo binding as well as the dynamic dynein-LIS1 interaction. Qiu et al. link the ATPase cycle at the AAA3 domain of cytoplasmic dynein to the spatial regulation of dynein in fungal cells. Specifically, the AAA3 ATPase cycle allows dynein to accumulate at the microtubule plus ends before being activated by cargo adapters, dynactin and LIS1; It also allows LIS1 to dissociate from dynein after its activation.
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