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

Ut Southwestern Medical Center, Dallas TX

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Abstract

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.