THESIS
2013
Abstract
Phototransduction cascade in Drosophila is the fastest known G-protein coupled cascade.
In Drosophila photoreceptor cells, INAD is a scaffold protein that organizes the key signaling
proteins in an assembly that enables the fast, efficient signaling process. Among the five
INAD PDZ domains, a dynamic disulfide bond in PDZ5 plays a crucial role in light-induced
activation/deactivation process. However the disulfide redox potential indicates that the
oxidized state is extremely stable and cannot complete the redox cycle completely. Another
research revealed that the coupling of the fourth and fifth PDZ domains can raise the redox
potential remarkably by ~330 mV and keep PDZ5 in the reduced state. Acidification by PLC-mediated
PIP2 hydrolysis helps decouple PDZ45 complex so that th...[
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Phototransduction cascade in Drosophila is the fastest known G-protein coupled cascade.
In Drosophila photoreceptor cells, INAD is a scaffold protein that organizes the key signaling
proteins in an assembly that enables the fast, efficient signaling process. Among the five
INAD PDZ domains, a dynamic disulfide bond in PDZ5 plays a crucial role in light-induced
activation/deactivation process. However the disulfide redox potential indicates that the
oxidized state is extremely stable and cannot complete the redox cycle completely. Another
research revealed that the coupling of the fourth and fifth PDZ domains can raise the redox
potential remarkably by ~330 mV and keep PDZ5 in the reduced state. Acidification by PLC-mediated
PIP2 hydrolysis helps decouple PDZ45 complex so that the isolated PDZ5 is readily
oxidized. In Chapter 1 of this thesis, theoretical investigation focuses on the conformation-coupled
redox regulation mechanism of PDZ45 complex using molecular dynamics
simulations and statistical analyses, and we propose an allosteric pathway through which the
conformational changes upon coupling are conveyed.
Membrane-associated guanylate kinases (MAGUKs) are a large family of scaffold
proteins that play critical roles in synaptic development and activities. Each member of
MAGUKs contains a guanylate kinase (GK) domain. The GMP-binding pocket of DLG GK
domains inherited from yeast GK enzyme has lost the catalytic function but evolved into a
phosphorylation-specific binding pocket. In Chapter 2, we have performed docking calculations and virtual screening of small molecules targeting the phospho-binding site of
DLG GK domain with an aim to discover potential lead compounds which can be developed into drugs for MAGUK-related mental disorder diseases, and to understand the patterns and
mechanism of binding interactions from theoretical perspective.
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