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

说明书(由申请人提供)：newitin发出的信号需要接头蛋白Nck和肌动蛋白成核促进因子N-WASP来刺激有效的肾小球功能所必需的肌动蛋白聚合。这一信号通路的中断会导致肾病综合征，其特征是蛋白异常分泌到尿液中，最终导致终末期肾功能衰竭。蛋白质的聚集性对于有效的信号传递是很重要的，尽管还缺乏机制上的理论基础。我们实验室的研究发现了一种通过二聚化来调节N-WASP活性的新方法，它可以将N-WASP的体外活性提高100倍。我们假设NCK聚簇调节N-WASP二聚体在neparin信号中的作用，这是我们打算研究的。 与公共卫生相关：蛋白质的聚集被认为对正常的肾脏功能很重要，因为它潜在地调节了蛋白质的活性。两种蛋白质，neparin和Nck，与一系列肾脏疾病有关，这些疾病最终可能导致肾衰竭。我们认为，两个蛋白质newitin和Nck的聚集调节另一种蛋白质N-WASP的二聚化和活性，该蛋白质参与肌动蛋白的聚合。

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.