THESIS
2018
xi, 61 pages : color illustrations ; 30 cm
Abstract
Discs large (DLG) MAGUKs are abundantly expressed in glutamatergic synapses, crucial
for synaptic transmission, and plasticity by anchoring various postsynaptic components
including glutamate receptors, downstream scaffold proteins and signaling enzymes. Different
DLG members have shared structures and functions, but also contain unique features. How
DLG family proteins function individually and cooperatively is largely unknown.
Here, we report that PSD-95 PDZ3 directly couples with SH3–GK tandem in a PDZ ligand
binding-dependent manner, and the coupling can promote PSD-95 dimerization and
multimerization. Aided by sortase-mediated protein ligation and selectively labeling, we
elucidated the PDZ3/SH3–GK conformational coupling mechanism using NMR spectroscopy.
We further demons...[
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Discs large (DLG) MAGUKs are abundantly expressed in glutamatergic synapses, crucial
for synaptic transmission, and plasticity by anchoring various postsynaptic components
including glutamate receptors, downstream scaffold proteins and signaling enzymes. Different
DLG members have shared structures and functions, but also contain unique features. How
DLG family proteins function individually and cooperatively is largely unknown.
Here, we report that PSD-95 PDZ3 directly couples with SH3–GK tandem in a PDZ ligand
binding-dependent manner, and the coupling can promote PSD-95 dimerization and
multimerization. Aided by sortase-mediated protein ligation and selectively labeling, we
elucidated the PDZ3/SH3–GK conformational coupling mechanism using NMR spectroscopy.
We further demonstrated that PSD-93, but not SAP102, can also undergo PDZ3 ligand binding-induced
conformational coupling with SH3–GK and form homo-oligomers. Interestingly, PSD-95 and PSD-93 can also form ligand binding-induced hetero-oligomers, suggesting a
cooperative assembly mechanism for the mega-N-methyl-d-aspartate receptor synaptic
signaling complex. Finally, we provide evidence showing that ligand binding-induced
conformational coupling between PDZ and SH3–GK is a common feature for other MAGUKs
including CASK and PALS1.
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