Nov 5, 2018

Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

BioRxiv : the Preprint Server for Biology
Nils RademacherSarah A. Shoichet

Abstract

PSD-95 MAGUK family scaffold proteins are multi-domain organisers of synaptic transmission that contain three PDZ domains followed by an SH3-GK domain tandem. This domain architecture allows coordinated assembly of protein complexes composed of neurotransmitter receptors, synaptic adhesion molecules, cytoskeletal proteins and downstream signalling effectors. Here we show that binding of monomeric PDZ3 ligands to the third PDZ domain of PSD-95 induces functional changes in the intramolecular SH3-GK domain assembly that influence subsequent homotypic and heterotypic complex formation. We identify PSD-95 interactors that differentially bind to the SH3-GK domain tandem depending on its conformational state. Among these interactors we further establish the heterotrimeric G protein subunit Gnb5 as a PSD-95 complex partner at dendritic spines. The PSD-95 GK domain binds to Gnb5 and this interaction is triggered by PDZ3 ligands binding to the third PDZ domain of PSD-95, unraveling a hierarchical binding mechanism of PSD-95 complex formation.

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Mentioned in this Paper

Guanosine
DLG4
Presynaptic density protein 95
Complex (molecular entity)
Dlgh4 protein, mouse
Synaptic Transmission
Scaffold protein
DLG4 wt Allele
Tandem
Binding (Molecular Function)

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