Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

ELife
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 and downstream signalling effectors. Here we show that binding of monomeric CRIPT-derived 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 of rat hippocampal neurons. The PSD-95 GK domain binds to Gnb5, and this interaction is triggered by CRIPT-derived 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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Citations

Sep 16, 2020·Proceedings of the National Academy of Sciences of the United States of America·Louise LaursenPer Jemth
Mar 12, 2020·Molecular Neurobiology·Anton OmelchenkoBonnie L Firestein
May 18, 2020·Proceedings of the National Academy of Sciences of the United States of America·Mark J Khoury, David Bilder
Apr 2, 2021·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Emmanuel PrikasArne Ittner
Sep 20, 2021·Protein Science : a Publication of the Protein Society·Yonghong ZhangJames B Ames
Sep 9, 2021·Molecular Biology of the Cell·Katherine A SharpDavid Bilder

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Methods Mentioned

BETA
flow cytometry
Fluorescence
amino acid exchange
coIP
targeted mutation
NMR
coimmunoprecipitation
transfection
pull-downs
pull-down

Software Mentioned

Mascot Distiller Quantitation Toolbox
ImageQuant TL

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