Determining the Structural Topology of Nephrin-Receptor-Signaling-Complexes

确定去氧肾上腺素受体信号复合物的结构拓扑

• 批准号: 8203019
• 负责人: Chi Won Pak
• 金额: $ 4.84万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203019
• 关键词: Actins; Adaptor Signaling Protein; Address; Biochemical; Cells; Chronic Kidney Failure; Complex; Dimerization; End stage renal failure; Fluorescence Resonance Energy Transfer; Integral Membrane Protein; Kidney Diseases; Kidney Failure; Lead; Measures; Methods; Molecular; N-WASP protein; NCK adaptor protein 1; Nephrotic Syndrome; Protein Secretion; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Renal function; SH3 Domains; Signal Pathway; Signal Transduction; Tail; Testing; Urine; base; density; glomerular function; in vitro activity; nephrin; novel; podocyte; polymerization

DESCRIPTION (provided by applicant): Signaling by nephrin requires the adaptor protein, Nck, and the actin nucleation-promoting factor, N-WASP, to stimulate actin polymerization necessary for efficient glomerular function. Disruptions to this signaling pathway result in nephrotic syndromes, which are characterized by abnormal secretion of protein into urine and ultimately end-stage renal failure. Clustering of the proteins, nephrin and Nck, have been suggested to be important for efficient signaling, though a mechanistic rationale for this is lacking. Studies from our lab have identified a novel regulation of N-WASP activity through dimerization, which increases N-WASP's activity in vitro by >100- fold. We hypothesize that Nck clustering regulates N-WASP dimerization in nephrin signaling, which we propose to study. PUBLIC HEALTH RELEVANCE: The clustering of proteins has been suggested to be important for proper kidney function, by potentially regulating protein-activity. Two proteins, nephrin and Nck, are relevant to a spectrum kidney diseases that may ultimately lead to kidney failure. We propose that the clustering of the two proteins, nephrin and Nck, regulates the dimerization and activity of another protein, N-WASP, that is involved in the polymerization of actin.

描述（由申请人提供）：nephrin的信号传导需要衔接蛋白Nck和肌动蛋白成核促进因子N-WASP刺激有效肾小球功能所必需的肌动蛋白聚合。对该信号通路的破坏导致肾病综合征，其特征在于蛋白质异常分泌到尿中并最终导致终末期肾衰竭。蛋白质，nephrin和Nck的聚类，已被认为是重要的有效的信号，虽然这是缺乏一个机制的理由。我们实验室的研究已经确定了一种通过二聚化来调节N-WASP活性的新方法，它使N-WASP的体外活性增加了100倍以上。我们假设，Nck集群调节nephrin信号，我们建议研究的N-WASP二聚化。 公共卫生关系：已经表明蛋白质的聚集通过潜在地调节蛋白质活性对于适当的肾功能是重要的。两种蛋白质nephrin和Nck与可能最终导致肾衰竭的一系列肾脏疾病相关。我们建议，这两种蛋白质，nephrin和NCK的集群，调节二聚化和活性的另一种蛋白质，N-WASP，这是参与肌动蛋白的聚合。