Primary cilia organize signaling pathways such as vision, olfaction and Hedgehog signaling. Proper functioning of these pathways is critically dependent on the movements of molecules into, inside and out of cilia, yet our understanding of the basic mechanisms governing trafficking through cilia remains fragmentary. Past work from the lab identified and characterized the BBSome, a protein complex that ferries signaling receptors out of cilia and clears photoreceptor outer segments of unwanted proteins. The relevance of the BBSome to human health and disease is evidence by the fact that BBSome dysfunction causes Bardet-Biedl Syndrome (BBS), a hereditary disease characterized by obesity, retinal degeneration, polydactyly and kidney malformations. The major goal of this proposal is to determine the structure and function of the molecular cogs and levers within the BBSome that enable selective removal of proteins from cilia. The proposed studies will cast new light on ciliary trafficking and lay the basis of future therapeutic interventions.
Mutations in the BBSome, a protein complex that removes activated signaling receptors from cilia, typically result in Bardet-Biedl Syndrome, a hereditary disease characterized by obesity, retinal degeneration, polydactyly and kidney malformations, or more rarely in non-syndromic retinal dystrophies (NSRDs). Since there is currently no understanding of how different mutations result in very different diseases and since initial gene therapy attempts to treat BBS failed in preclinical trials, this proposal seeks to determine atomic structures of the BBSome by itself and in complex with effectors and cargoes to provide a solid basis to understand the function and regulation of the BBSome, to analyze how mutations in BBSome subunits cause disease, and to develop effective therapeutic interventions.
