The dynein-2 microtubule motor

人体中几乎所有细胞都有初级纤毛，这是一种类似天线的结构，从几乎所有细胞的表面出现。纤毛的形成和/或功能缺陷导致一系列被称为纤毛病的人类疾病。该项目并不寻求定义疾病的分子基础，而是完全针对对纤毛生物学的基本理解。纤毛对发育信号尤为重要，因此，动力蛋白-2支撑着体内所有细胞的正常功能。纤毛是围绕着富含微管的结构形成的，运动蛋白沿着微管结构运输分子。大量的工作已经表明，细胞质动力蛋白-2运动复合体对正常的人类发育是必不可少的，因为它既能引导分子进入纤毛，又能控制分子沿着纤毛运动。动力蛋白-2与动力蛋白-1有远亲关系，动力蛋白-1是一种复合物，在功能方面，尤其是在其组成方面，人们对它的了解相对较好。这两种“细胞质”动力蛋白在细胞内移动大分子复合物，与驱动纤毛和鞭毛跳动的“轴突”动力蛋白不同。与轴突动力蛋白和细胞质动力蛋白-1相比，直到最近，我们对构成动力蛋白-2机器的单个蛋白质知之甚少。在这里，我建议以我们的工作为基础，第一次定义了人类动力蛋白-2复合物的生化组成。建立在连接膜运输和微管马达的强大工作记录的基础上，我建议使用生物化学，先进的细胞成像和选择性蛋白质组学的结合来提供细胞中动力蛋白-2的基本生物学的明确定义。

Nearly all cells in the human body build a primary cilium, an antenna-like structure that emerges from the surface of nearly all human cells. Defects in the formation and/or function of the cilium lead to a cohort of human diseases known as the ciliopathies. This project does not seek to define the molecular basis of disease but instead is solely directed at a fundamental understanding o cilia biology. Cilia are of particular importance for developmental signalling and therefore, dynein-2 underpins the normal function of all cells in the body. Cilia are built around a microtubule rich structure along which molecules are transported by motor proteins. Considerable work has now shown that the cytoplasmic dynein-2 motor complex is essential for normal human development because of its function in both directing molecules into cilia as well as controlling their movement along cilia. Dynein-2 is distantly related to dynein-1, a complex that is relatively well understood in terms of function and particularly well in terms of its composition. These two "cytoplasmic" dyneins move large molecular complexes around inside cells and are distinct from the "axonemal" dyneins that drive beating of cilia and flagella. In contrast to the axonemal dyneins and to cytoplasmic dynein-1, until very recently we have known little about the individual proteins that go to make up the dynein-2 machine. Here, I propose to build on our work that has, for the first time, defined the biochemical composition of the human dynein-2 complex. Building on a strong track record of work linking membrane trafficking and microtubule motors, I propose to use a combination of biochemistry, advanced cell imaging, and selective proteomics to provide a clear definition of the fundamental biology of dynein-2 in cells.