Intramolecular domain dynamics regulate synaptic MAGUK protein interactions.

Authors :: Rademacher N
Kuropka B
Kunde SA
Wahl MC
Freund C
Shoichet SA
Source :: ELife [Elife] 2019 Mar 13; Vol. 8. Date of Electronic Publication: 2019 Mar 13.
Publication Year :: 2019
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 and downstream signalling effectors. Here we show that binding of monomeric CRIPT-derived PDZ <subscript>3</subscript> 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 of rat hippocampal neurons. The PSD-95 GK domain binds to Gnb5, and this interaction is triggered by CRIPT-derived PDZ <subscript>3</subscript> ligands binding to the third PDZ domain of PSD-95, unraveling a hierarchical binding mechanism of PSD-95 complex formation.<br />Competing Interests: NR, BK, SK, MW, CF, SS No competing interests declared<br /> (© 2019, Rademacher et al.)