Dynamic Scaffolding in a G-Protein Signaling Cascade




Mishra, Prashant

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The InaD scaffold organizes a multi-protein complex that is essential for proper visual signaling in Drosophila photoreceptor cells. Here we show that one of the InaD PDZ domains (PDZ5) exists in a redox-dependent equilibrium between two conformations- a reduced form which is similar to the structure of other PDZ domains, and an oxidized form in which the ligand-binding site is distorted through formation of a strong intramolecular disulfide bond. We demonstrate transient light-dependent formation of this disulfide bond in vivo, and find that transgenic flies expressing a mutant InaD in which PDZ5 is locked in the reduced state display severe defects in termination of visual responses and visually-mediated reflex behavior. These studies demonstrate a novel conformational switch mechanism for PDZ domain function and suggest that InaD behaves more like a dynamic machine rather than a passive scaffold, regulating signal transduction at the millisecond timescale through cycles of conformational change.

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The file named "mishraprashant.pdf" is the primary dissertation file. Supplemental movie files ("Mishra_Movie_S1.mpg", "Mishra_Movie_S2.mpg") are also available.

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