Intramolecular domain dynamics regulate synaptic MAGUK protein interactions.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30864948.
- Also identified by DOI 10.7554/eLife.41299 and PMC identifier 6438691.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>3</sub> 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<sub>3</sub> ligands binding to the third PDZ domain of PSD-95, unraveling a hierarchical binding mechanism of PSD-95 complex formation.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Disks Large Homolog 4 Protein
- GTP-Binding Protein beta Subunits
- Protein Multimerization
- Synapses