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

基本信息

批准号：
8053279
负责人：
Vadim Y Arshavsky
金额：
$ 18.72万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8053279
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 Light 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

项目摘要

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感光器外节功能中的作用。膜细胞骨架装饰基本上所有细胞类型的质膜，为它们提供机械支撑并将选定的膜蛋白保留在专门的膜子域内。令人惊讶的是，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，当时我们报道了环核苷酸门控通道2-亚基的外段靶向关键取决于其与膜细胞骨架蛋白的相互作用锚蛋白 G。我们现在提出，锚蛋白 G 的另一个主要功能是将该通道和其他蛋白质保留在杆外节质膜上，并防止它们分类到感光盘中。在目标 1 中，我们将在环核苷酸门控通道的情况下测试这一假设。在目标 2 中，我们将寻找杆外节中的其他锚蛋白 G 结合伴侣。我们还将测试杆中其他蛋白质的选择性质膜定位是否依赖于它们与锚蛋白 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，以建立一个更大的项目，专门用于了解膜细胞骨架在光感受器健康和疾病中的作用。公共健康相关性：本申请提出的研究涉及负责感光细胞感光区（外节）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一些最严重类型的遗传性视网膜退行性疾病，包括但不限于色素性视网膜炎。这凸显了了解蛋白质运输到外段及其随后组装成大型功能复合物的机制的重要性。阐明这些机制对于制定疾病预防和未来治疗干预策略至关重要。