Key Points
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The postsynaptic density (PSD) is a large, dynamic protein assembly that orchestrates the densities and activities of both AMPA-type and NMDA-type glutamate receptors in excitatory synapses.
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The membrane-associated guanylate kinase (MAGUK) family of scaffold proteins, including Discs large homologues (DLGs) and membrane-associated guanylate kinase inverted (MAGI) proteins, are key organizers of PSDs. They act as an interface between the upstream membrane-spanning glutamate receptors and cell adhesion proteins and the downstream synapse-associated protein 90/postsynaptic density protein 95 (PSD95)-associated protein (SAPAP)–SRC homology 3 (SH3) and multiple ankyrin repeat domains protein (SHANK) complexes and the cytoskeleton.
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The guanylate kinase-like (GK) domain of MAGUKs binds to target proteins in a phosphorylation-dependent manner. This phosphorylation-dependent target recognition by MAGUKs suggests that the assembly of PSD is activity-dependent.
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Each MAGUK contains a highly conserved domain organization with PSD95–DLG1–Zonula occludens 1 (PDZ)–SH3–GK domains arranged in tandem. The PDZ–SH3–GK tandem forms a supramodule allowing the MAGUK scaffolds to bind to target proteins with high specificity as well as to cluster transmembrane ion channels and receptors.
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Biochemical and structural studies of MAGUKs have offered insights into why mutations affecting genes encoding MAGUKs and their target proteins may alter synaptic protein organization and lead to defects of synaptic development and signalling.
Abstract
Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are highly enriched in synapses and are responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Mutations in genes encoding MAGUKs and their interacting proteins can cause a broad spectrum of human psychiatric disorders. Here, we review MAGUK-mediated synaptic protein complex formation and regulation by focusing on findings from recent biochemical and structural investigations. These mechanistic-based studies show that the formation of MAGUK-organized complexes is often directly regulated by protein phosphorylation, suggesting a close connection between neuronal activity and the assembly of dynamic protein complexes in synapses.
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Acknowledgements
Research in the laboratory of M.Z. has been supported by grants from the Research Grants Council of Hong Kong (663811, 663812 and AoE-M09-12) and a 973 Program grant from the Minister of Science and Technology of China (2014CB910204). J.Z. is supported by a grant from the National Natural Science Foundation of China (31470733). M.Z. is a Kerry Holdings Professor in Science and a Senior Fellow of the Institute for Advanced Study (IAS) at the Hong Kong University of Science and Technology (HKUST).
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Supplementary information
Supplementary information S1 (Figure)
a | The structure of PKC-ι in complex with a substrate peptide derived from PAR3 (PDB code: 4DC2). (PDF 532 kb)
Supplementary information S2 (Figure)
a | Ribbon diagram of the SAP97 SH3–GK tandem (PDB code: 3UAT). (PDF 532 kb)
Glossary
- Dendritic remodelling
-
A biochemical process of dendritic spines in which the actin cytoskeleton undergoes a rapid change in shape and structure in response to various stimuli.
- Multivalency effect
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Binding avidity enhancement brought by synergistic actions of individual interaction sites between multi-domain scaffold protein and multivalent target interactions.
- Allosteric regulation
-
Binding of an effector molecule to a specific site of a protein causes conformational changes far away from the binding site and thus alters the function of the protein.
- Phosphoprotein-binding modules
-
Protein domains such as the SH2 domain, the GK domain and the FHA domain that can specifically recognize phosphorylated proteins.
- Supramodules
-
Two or more protein modules arranged in tandem in a protein that interact with each other to form a high-order structure with functions distinct from those of the individual or simple sum of the modules.
- Domain-swapped dimer
-
Two identical protein molecules associate to form dimer by exchanging identical structural elements, such that native intramolecular interactions are replaced by their intermolecular counterparts.
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Zhu, J., Shang, Y. & Zhang, M. Mechanistic basis of MAGUK-organized complexes in synaptic development and signalling. Nat Rev Neurosci 17, 209–223 (2016). https://doi.org/10.1038/nrn.2016.18
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DOI: https://doi.org/10.1038/nrn.2016.18
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