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Principles of membrane-receptor organization by cytoplasmic ligands

Nanometer to micron-sized clusters of membrane receptors are widely observed in cells. However, the mechanisms by which such clustering is achieved are not completely understood, in part because of the lack of in-vitro reconstitution of these clusters.

Sudeep Banjade Research Image

I am interested in the general question of how cytoplasmic effectors cluster and organize membrane receptors, and how this organization helps in amplifying downstream signaling. For this purpose, I am studying Nephrin, a transmembrane protein found in podocytes, the epithelial cells of the kidney. Nephrin’s cytoplasmic domain has three phosphotyrosine motifs, which, upon phosphorylation, recruit the adaptor protein Nck via its SH2 domain. In addition to the SH2 domain, Nck has three SH3 domains, which recruit N-WASP via its multiple proline-rich motifs.

N-WASP is a member of the WASP family of actin nucleation promoting factors. I recently discovered that phosphorylated Nephrin, Nck and N-WASP phase-separate in 3D solution, and also form micron-sized clusters on supported lipid bilayers. This phenomenon appears to occur due to the polymerization induced by the multivalent interactions of the phosphotyrosine motifs, the SH3 domains, and the proline-rich motifs.

I am using this model-system to delineate the mechanisms used by adaptor proteins to regulate clustering of membrane receptors via polymerization and phase separation, and how such clustering temporally and spatially regulates actin assembly.

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