Ankyrin G in protein sorting between rod plasma membrane and photoreceptor discs

锚蛋白 G 在杆质膜和感光盘之间的蛋白质分选中的作用

• 批准号: 7869100
• 负责人: Vadim Y Arshavsky
• 金额: $ 23.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869100
• 关键词: Address; Affect; Ankyrins; Antibodies; Apical; Binding; Biogenesis; Cattle; Cell membrane; Complex; Cytoskeleton; Degenerative Disorder; Detergents; Disease; Elements; Ensure; Epithelial Cells; Functional disorder; Funding; Future; Goals; Health; Immunoprecipitation; Inherited; Intracellular Membranes; Investigation; Knockout Mice; Maintenance; Mass Spectrum Analysis; Mechanics; Membrane; Membrane Proteins; Molecular; Morphogenesis; Photoreceptors; Positioning Attribute; Process; Protein Binding; Proteins; Reporter; Reporting; Retina; Retinitis Pigmentosa; Rhodopsin; Rod Outer Segments; Role; Secure; Sorting - Cell Movement; Testing; Therapeutic Intervention; cell type; cyclic-nucleotide gated ion channels; disorder prevention; insight; mutant; photoreceptor cell outer segment; photoreceptor disc; prevent; programs; protein transport; public health relevance; research study; retinal rods; tool; trafficking

DESCRIPTION (provided by applicant): The overall goal of this application is to explore the role of the membrane cytoskeleton in the functioning of photoreceptor outer segments. The membrane cytoskeleton decorates plasma membranes in essentially all cell types, providing them with mechanical support and retaining selected membrane proteins within specialized membrane sub-domains. Surprisingly, the role of the membrane cytoskeleton in photoreceptors had not been systematically addressed until very recently, when we reported that the outer segment targeting of the 2-subunit of the cyclic nucleotide-gated channel is critically dependent on its interaction with the membrane cytoskeleton protein ankyrin G. We now propose that another major function of ankyrin G is to retain this channel and other proteins at the rod outer segment plasma membrane and to prevent them from sorting into photoreceptor discs. In Aim 1 we will test this hypothesis for the case of the cyclic nucleotide-gated channel. In Aim 2 we will search for other ankyrin G binding partners in rod outer segments. We will also test whether selective plasma membrane localization of other proteins in rods is dependent on their binding to ankyrin G. We hope that the completion of this exploratory study will yield a sufficient body of information, concepts and experimental tools to build a larger program devoted to understanding the roles of the membrane cytoskeleton in photoreceptor health and disease. PUBLIC HEALTH RELEVANCE: The studies proposed in this application address the molecular and cellular mechanisms responsible for the biogenesis, maintenance and functioning of the light-sensitive compartment of the photoreceptor cells, the outer segment. Dysfunction of these processes causes some of the most severe types of inherited degenerative diseases of the retina, including but not limited to retinitis pigmentosa. This highlights the importance of understanding the mechanisms underlying the trafficking of proteins to the outer segment and their subsequent assembly into large functional complexes. Elucidating these mechanisms is essential for developing strategies for disease prevention and future therapeutic interventions.

描述（由申请人提供）：本申请的总体目标是探索膜细胞骨架在光感受器外部段功能中的作用。膜细胞骨架基本上在所有细胞类型中都装饰了质膜，从而为它们提供了机械支撑，并在专门的膜亚域内保留了选定的膜蛋白。令人惊讶的是，直到最近才报告，膜细胞骨架在光感受器中的作用直到最近才被系统地解决。在杆外段质膜上，以防止它们对光感受器盘排序。在AIM 1中，我们将对环状核苷酸门控通道的情况进行检验。在AIM 2中，我们将在杆外段搜索其他Ankyrin G结合伙伴。我们还将测试其他蛋白质中其他蛋白质的选择性质膜定位是否取决于它们与Ankyrin G的结合。我们希望这项探索性研究的完成将产生足够的信息，概念和实验工具，以建立一个较大的程序，致力于了解膜细胞骨架在光核能健康和疾病中的作用。 公共卫生相关性：本申请中提出的研究涉及负责光感受器细胞（外部段）光敏感室的生物发生，维持和功能的分子和细胞机制。这些过程的功能障碍会导致视网膜中一些最严重的遗传性退化性疾病，包括但不限于色素性视网膜炎。这突出了理解蛋白质运输到外部细分市场及其随后组装到大型功能复合物中的机制的重要性。阐明这些机制对于制定预防疾病和未来治疗干预措施的策略至关重要。