Mechanistic basis of maguk-organized complexes in synaptic development and signalling

KEY POINTS * 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. * 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. * 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. * 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. * 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. Access through your institution Buy or subscribe This is a preview of

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FOR SHAPING NEURONAL SYNAPSES Article 08 January 2021 TAU FORMS SYNAPTIC NANO-BIOMOLECULAR CONDENSATES CONTROLLING THE DYNAMIC CLUSTERING OF RECYCLING SYNAPTIC VESICLES Article Open access

10 November 2023 ACTIVITY DEPENDENT DISSOCIATION OF THE HOMER1 INTERACTOME Article Open access 25 February 2022 ACCESSION CODES ACCESSIONS PROTEIN DATA BANK * 1NF3 * 2KA9 * 2LC7 * 2QKT *

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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). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS

* Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Jinwei Zhu, Yuan Shang 

& Mingjie Zhang * Center of Systems Biology and Human Health, School of Science and Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay,

Kowloon, Hong Kong, China Mingjie Zhang * National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese

Academy of Sciences, 333 Haike Road, Pudong District, Shanghai, 201210, China Jinwei Zhu Authors * Jinwei Zhu View author publications You can also search for this author inPubMed Google

Scholar * Yuan Shang View author publications You can also search for this author inPubMed Google Scholar * Mingjie Zhang View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Mingjie Zhang. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS

DATABASES Protein Data Bank POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5

POWERPOINT SLIDE FOR FIG. 6 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 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. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 18 March 2016 * Issue Date: April 2016 * DOI:

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