MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density.

Nils Rademacher,Jennifer A Lardong,Markus C Wahl,Bettina Schmerl,Sarah A Shoichet

doi:10.1038/srep35283

Abstract

At neuronal synapses, multiprotein complexes of trans-synaptic adhesion molecules, scaffold proteins and neurotransmitter receptors assemble to essential building blocks required for synapse formation and maintenance. Here we describe a novel role for the membrane-associated guanylate kinase (MAGUK) protein MPP2 (MAGUK p55 subfamily member 2) at synapses of rat central neurons. Through interactions mediated by its C-terminal SH3-GK domain module, MPP2 binds to the abundant postsynaptic scaffold proteins PSD-95 and GKAP and localises to postsynaptic sites in hippocampal neurons. MPP2 also colocalises with the synaptic adhesion molecule SynCAM1. We demonstrate that the SynCAM1 C-terminus interacts directly with the MPP2 PDZ domain and that MPP2 does not interact in this manner with other highly abundant postsynaptic transmembrane proteins. Our results highlight a previously unexplored role for MPP2 at postsynaptic sites as a scaffold that links SynCAM1 cell adhesion molecules to core proteins of the postsynaptic density.

Highlights

Scaffold proteins are structural proteins that are essential for the assembly of functional protein complexes
In order to explore the possibility that MPP2 might be an important member of synaptic protein complexes, we examined the content of AMPA receptor complexes using immunoprecipitation
Since we could copurify MPP2 and PSD95 in a protein complex that is associated with AMPA receptors (Fig. 1a), and we observed colocalisation of MPP2 and postsynaptic density (PSD)-95 at postsynaptic sites in hippocampal neurons (Fig. 1b), we explored the interaction between MPP2 and PSD-95 in more detail

Summary

Introduction

Scaffold proteins are structural proteins that are essential for the assembly of functional protein complexes. In addition to serving as central interaction hubs for cytosolic proteins that are situated within the postsynapse[7], PSD-95 and related family members are important for synaptic targeting and regulated trafficking of neurotransmitter receptors[8,9]. This established function of PSD-95 relies on PDZ-ligand interactions between the N-terminal PDZ domains of PSD-95 and the PDZ-binding C-termini of specific receptor subunits[10]. We demonstrate that MPP2 colocalises with the synaptic cell adhesion molecule SynCAM1 ( sometimes referred to as CADM1, TSLC1, or Igsf4) and directly binds SynCAM1 via its PDZ domain, and highlight a novel structural link between the SynCAM1 cell adhesion complex and several core components of the PSD

Methods

Results

Conclusion