Structural basis of BBSome-mediated ciliary exit

项目摘要 初级纤毛组织信号通路，如视觉，嗅觉和刺猬信号。正常运作 这些途径的关键是依赖于运动的分子进入，内部和外部的纤毛，但我们的 对通过纤毛进行贩运的基本机制的了解仍然是零碎的。过去的工作 来自实验室的研究人员鉴定并表征了BBSome，这是一种蛋白质复合物， 纤毛和清除感光细胞外节的不需要的蛋白质。BBSome与人类的相关性 BBSome功能障碍导致Bardet-Biedl综合征（BBS），一种 以肥胖、视网膜退化、多指和肾畸形为特征的遗传性疾病。 这项建议的主要目标是确定分子齿轮和杠杆的结构和功能 在BBSome中，能够从纤毛中选择性地去除蛋白质。拟议中的研究将为我们提供新的视角， 纤毛贩运，并奠定了未来的治疗干预措施的基础。

PROJECT SUMMARY 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.