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

描述（由申请人提供）：肾素信号需要接头蛋白Nck和肌动蛋白成核促进因子N-WASP来刺激肌动蛋白聚合，这是有效肾小球功能所必需的。这种信号通路的破坏导致肾病综合征，其特征是蛋白质异常分泌到尿液中，最终导致终末期肾功能衰竭。聚类的蛋白质，nephrin和Nck，已被认为是重要的有效信号传导，尽管缺乏机制的基本原理。我们实验室的研究发现了一种通过二聚化调节N-WASP活性的新方法，该方法使N-WASP的体外活性提高了100倍。我们假设Nck聚类调节了nephrin信号传导中的N-WASP二聚化，我们建议对此进行研究。

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.