The dynein-2 microtubule motor

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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.