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

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。

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.