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Dynamic scaffolding in a G protein-coupled signaling system
Prashant Mishra1, Michael Socolich, Mark A Wall
1Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
Cell
|October 10, 2007
Summary
The INAD scaffold in Drosophila photoreceptors uses a redox-switch mechanism. This dynamic conformational change in PDZ5 regulates visual signaling and behavior at millisecond timescales.
Area of Science:
- Molecular and Cellular Biology
- Neuroscience
- Structural Biology
Background:
- The INAD scaffold is crucial for visual signal transduction in Drosophila photoreceptor cells, organizing essential multiprotein complexes.
- PDZ domains are known protein interaction modules, but their dynamic regulation remains an area of active investigation.
Purpose of the Study:
- To investigate the structural dynamics of the INAD scaffold, specifically focusing on the redox-dependent behavior of its PDZ domains.
- To elucidate the functional consequences of PDZ domain conformational changes on visual signaling and behavior in vivo.
Main Methods:
- X-ray crystallography to determine the structures of INAD PDZ domains in different redox states.
- In vivo biochemical assays to detect light-dependent disulfide bond formation.
- Generation and behavioral analysis of transgenic Drosophila expressing mutant INAD proteins.
Main Results:
- One INAD PDZ domain (PDZ5) undergoes a redox-dependent conformational switch between reduced and oxidized states.
- The oxidized state features a distorted ligand-binding site due to an intramolecular disulfide bond, which forms transiently upon light exposure in vivo.
- Flies with a PDZ5 mutant locked in the reduced state exhibit severe defects in visual response termination and visually guided behaviors.
Conclusions:
- INAD functions as a dynamic molecular machine, not a static scaffold, utilizing conformational switching for signal regulation.
- Redox-dependent conformational changes in PDZ domains provide a mechanism for millisecond-timescale regulation of signal transduction.
- This study reveals a novel mechanism of PDZ domain regulation with implications for understanding dynamic protein complex function in signaling pathways.
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