A Functional Role of Postsynaptic Density-95-Guanylate Kinase-Associated Protein Complex in Regulating Shank Assembly and Stability to Synapses
Open accessAbstract
Postsynaptic density (PSD) proteins include scaffold, cytoskeletal, and signaling proteins that structurally and functionally interact with glutamate receptors and other postsynaptic membrane proteins. The molecular mechanisms regulating the assembly of PSD proteins and their associations with synapses are still widely unknown. We investigated the molecular mechanisms of Shank1 targeting and synapse assembly by looking at the function of guanylate kinase-associated protein (GKAP) and PSD-95 interactions. Shank1 when it is not associated to GKAP, which binds to the Shank PSD-95-Discs Large-zona occludens-1 domain, forms filamentous and fusiform structures in which the Src homology 3 domain specifically interacts with the ankyrin repeat domain, thus allowing its multimerization via a novel form of intermolecular interaction. Surprisingly, in both COS-7 cells and hippocampal neurons, GKAP forms insoluble aggregates with Shank that colocalize with heat shock protein 70 and neurofilaments, two markers of the aggresomes in which misfolded proteins accumulate. However, the two proteins are organized in clusters in COS cells and synaptic clusters in neurons when both are overexpressed and associated with wild-type PSD-95, but not with palmitoylation-deficient PSD-95. Synaptic activity in neurons induces the formation of Shank and GKAP intracellular aggregation and degradation. Similarly, the overexpression of a GKAP mutant that is incapable of binding PSD-95 induces Shank aggregation and degradation in neurons. Our data suggest a possible functional and structural role of the PSD-95-GKAP complex in Shank and PSD protein assembly and stability to synapses.
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The relatedness of SHANK2 to SHANK3, involvement of SYNGAP1 in intellectual disability, and interaction of DLGAP family proteins with SHANK proteins further support their role in ASDs.
“The relatedness of SHANK2 to the causal ASD gene SHANK3 (ref. 5), involvement of SYNGAP1 in intellectual disability 19 , and interaction of DLGAP family proteins with SHANK proteins 20 further support their role in ASDs.”
From Functional impact of global rare copy number variation in autism spectrum disorders (2010) · cites this paper as [20]
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- Authors
- Romorini, S., Piccoli, G., Jiang, M., Grossano, P., Tonna, N., Passafaro, M., Zhang, M., & Sala, C.
- Affiliations
- University of Milan (IT)
- Hong Kong University of Science and Technology (HK)
- Corresponding author
- Sala, Carlo
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-10-20
- Volume
- 24
- Issue
- 42
- Pages
- 9391-9404
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6730104
- OpenAlex
- W2094379124
- Cited by
- 96
- References
- 5
- Citations by year
- 2026: 2 · 2025: 1 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 6 · 2016: 2 · 2015: 4 · 2014: 3 · 2013: 6 · 2012: 9
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Giovanni Armenise-Harvard Foundation
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Shank1, PSD-95, postsynaptic density, synapse assembly, protein aggregation, aggresomes, HSP70, neurofilaments, Src homology 3 domain, ankyrin repeat domain, protein oligomerization, palmitoylation, hippocampal neurons, synaptic activity
- MeSH terms
- SAP90-PSD95 Associated Proteins, Disks Large Homolog 4 Protein, Animals, Cells, Cultured, Chlorocebus aethiops, Cytoskeleton, Hippocampus, Humans, Membrane Proteins, Nerve Tissue Proteins, Neurons, Protein Binding, Recombinant Fusion Proteins, Synapses, Protein Structure, Tertiary, COS Cells, Amino Acid Motifs, Protein Transport, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Dendritic Spines, Rats
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