A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density

Ward G Walkup,Jost Vielmetter,Rebecca Hu,Mary B Kennedy,Meera Reghunathan,Ariella Iancu,Leslie T Schenker,Tara L Mastro,Barry Dylan Bannon

doi:10.7554/elife.16813

Ward G Walkup, Jost Vielmetter + Show 7 more

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https://doi.org/10.7554/elife.16813

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Abstract

SynGAP is a Ras/Rap GTPase-activating protein (GAP) that is a major constituent of postsynaptic densities (PSDs) from mammalian forebrain. Its α1 isoform binds to all three PDZ (PSD-95, Discs-large, ZO-1) domains of PSD-95, the principal PSD scaffold, and can occupy as many as 15% of these PDZ domains. We present evidence that synGAP-α1 regulates the composition of the PSD by restricting binding to the PDZ domains of PSD-95. We show that phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Polo-like kinase-2 (PLK2) decreases its affinity for the PDZ domains by several fold, which would free PDZ domains for occupancy by other proteins. Finally, we show that three critical postsynaptic signaling proteins that bind to the PDZ domains of PSD-95 are present in higher concentration in PSDs isolated from mice with a heterozygous deletion of synGAP.

Highlights

We propose a new model for regulation of trapping of AMPARs and other synaptic proteins in ’slots’ at the postsynaptic membrane
It builds on previous findings that the postsynaptic densities (PSDs) scaffold, in particular the PSD-95 complex, is dynamically regulated by activity (Gray et al, 2006; Sturgill et al, 2009), that activation of NMDA-type glutamate receptors (NMDARs) and calmodulin-dependent protein kinase II (CaMKII) leads to enhanced trapping of AMPARs within the PSD by binding to PDZ domains of PSD-95 (Opazo et al, 2010; 2012), and that synGAP moves away from the PSD after phosphorylation by CaMKII (Yang et al, 2013; Araki et al, 2015)
We propose that binding of the C-terminus of synGAP-a1 to the PDZ domains of PSD-95 restricts binding of TARPs, LRRTM2, neuroligin-2, and perhaps additional proteins

Summary

Introduction

We propose a new model for regulation of trapping of AMPARs and other synaptic proteins in ’slots’ at the postsynaptic membrane. The PDZ domains of PSD-95 act as docking sites for several synaptic regulatory proteins (Figures 1 and 2B); including NMDA-type glutamate receptors (NMDARs; Kornau et al, 1995), as well as neuroligins (Varoqueaux et al, 2006) and LRRTMs (Leucine Rich Repeat TransMembrane proteins; Linhoff et al, 2009), which nucleate new synapse formation and contribute to clustering of AMPARs (Siddiqui et al, 2010). AMPARs, NMDARs, TARPs, LRRTMs, and neuroligins comprise the most highly enriched transmembrane proteins precipitated together with PSD-95 from the PSD fraction of mouse forebrain (Dosemeci et al, 2007).The multiplicity of PDZ binding proteins at the synapse raises the question of whether and how competition for binding to the PDZ domains is regulated at individual synapses

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