Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
Department of Molecular and Cellular Biology, University of California-Davis, Davis, CA, USA.
Nat Struct Mol Biol. 2018 Mar;25(3):203-207. doi: 10.1038/s41594-018-0027-7. Epub 2018 Feb 7.
Cytoplasmic dynein is a protein complex that transports molecular cargo along microtubules (MTs), playing a key role in the intracellular trafficking network. Vertebrate dynein's movement becomes strikingly enhanced upon interacting with dynactin and a cargo adaptor such as BicaudalD2. However, the mechanisms responsible for increased transport activity are not well understood, largely owing to limited structural information. We used cryo-electron tomography (cryo-ET) to visualize the 3D structure of the MT-bound dynein-dynactin complex from Mus musculus and show that the dynactin-cargo adaptor complex binds two dimeric dyneins. This configuration imposes spatial and conformational constraints on both dynein dimers, positioning the four motor domains in proximity to one another and oriented toward the MT minus end. We propose that grouping multiple dyneins onto a single dynactin scaffold promotes collective force production, increased processivity, and unidirectional movement, suggesting mechanistic parallels to axonemal dynein. These findings provide structural insights into a previously unknown mechanism for dynein regulation.
细胞质动力蛋白是一种沿着微管（MTs）运输分子货物的蛋白质复合物，在细胞内运输网络中起着关键作用。脊椎动物动力蛋白与动力蛋白激活蛋白和货物衔接蛋白（如 BicaudalD2）相互作用后，其运动能力显著增强。然而，增加运输活性的机制尚不清楚，这主要是由于结构信息有限。我们使用冷冻电子断层扫描（cryo-ET）技术可视化了来自 Mus musculus 的 MT 结合的动力蛋白-动力蛋白激活蛋白复合物的 3D 结构，并表明动力蛋白激活蛋白-货物衔接蛋白复合物结合了两个二聚体动力蛋白。这种构象对两个动力蛋白二聚体施加了空间和构象限制，将四个马达结构域彼此靠近并朝向 MT 的 minus 端取向。我们提出，将多个动力蛋白聚集到单个动力蛋白激活蛋白支架上可以促进集体力的产生、增加的连续性和单向运动，这表明与轴丝动力蛋白具有机制上的相似性。这些发现为动力蛋白调节的一个以前未知的机制提供了结构见解。
