Is CEP290 a vesicle tether at the ciliary base?

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In order to function, cells need to sense their environment, manipulate their surroundings and move. For example, sperm cells swim using a whip-like tail; the cells lining your airways sweep mucus up into your throat, keeping your lungs clear; rod and cone cells in your retina collect light, allowing you to see; and the cells in your kidneys sense the flow of urine. These diverse functions are all performed by various types of cilia, which are finger-like organelles on the surface of cells. Cilia are found in many different organisms, from single-celled algae, to flies and humans. This shows that they evolved a very long time ago and are so useful that they have been retained and repurposed for a multitude of different biological functions during evolution.This proposal focuses on a protein called CEP290, which is one of the largest proteins in cilia. CEP290 is essential for the correct formation and function of cilia. When this protein is defective or missing from cells entirely cilia do not form correctly, and when they do, they have the wrong composition, which compromises their function. However, we don't understand what this protein actually does. We know very little about its structure, how it interacts with other cellular components, and how its organisation allows it to function. Cells are full of tiny membrane-bound "bubbles", called vesicles, that transport cellular components from one part of the cell to the other. The cell uses vesicles to generate cilia and, once formed, "feed" them with the components they need to function properly. Based on similarities with other proteins in the cell, we think that CEP290 is a "vesicle tether", whose role is to capture vesicles that contain cilium components and guide them to their destination at the cilium base. In this proposal we will investigate this hypothesis by investigating the molecular structure of CEP290, studying its binding to vesicles in vitro and inside cells, and how this function relies on its interactions with membranes and other cilium proteins. This will provide essential new insights into the molecular details of how cilia form and function.Genetic mutations in CEP290 cause a very broad range of inherited disorders. This tells us that CEP290 does something very important in cilia, and hence that we need to know what it does and how it does it to understand how cilia work. As cilia and CEP290 are found in such a wide range of organisms, from algae to humans, this will have wide-ranging implications for biology. Thankfully, human diseases caused by CEP290 mutations are rare in general, since both parents must carry a disease-causing mutation to produce children with a CEP290-related disorder (i.e. these disorders are recessive). However, the incidence of these disorders is much higher in consanguineous communities, which are often experience healthcare inequality and do not benefit fully from research. Thus, understanding how CEP290 mutations cause disease will help improve genetic counselling and develop gene therapies to prevent and treat these conditions, which is an important clinical and societal unmet need.