Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs
Open accessAbstract
The PSD-95/SAPAP/Shank complex functions as the major scaffold in orchestrating the formation and plasticity of the post-synaptic densities (PSDs). We previously demonstrated that the exquisitely specific SAPAP/Shank interaction is critical for Shank synaptic targeting and Shank-mediated synaptogenesis. Here, we show that the PSD-95/SAPAP interaction, SAPAP synaptic targeting, and SAPAP-mediated synaptogenesis require phosphorylation of the N-terminal repeat sequences of SAPAPs. The atomic structure of the PSD-95 guanylate kinase (GK) in complex with a phosphor-SAPAP repeat peptide, together with biochemical studies, reveals the molecular mechanism underlying the phosphorylation-dependent PSD-95/SAPAP interaction, and it also provides an explanation of a PSD-95 mutation found in patients with intellectual disabilities. Guided by the structural data, we developed potent non-phosphorylated GK inhibitory peptides capable of blocking the PSD-95/SAPAP interaction and interfering with PSD-95/SAPAP-mediated synaptic maturation and strength. These peptides are genetically encodable for investigating the functions of the PSD-95/SAPAP interaction in vivo.
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Actin is largely excluded from the core of the PSD, interacting with proteins such as Shank and SAPAP in the pallium.
“However, actin is largely excluded from the core of the PSD, interacting with such proteins as Shank and SAPAP located in the deeper, cytoplasmic-facing layer of the PSD referred to as the pallium (66, 162, 322).”
From Synaptic memory and CaMKII (2023) · cites this paper as [322]
The Discussion (page unavailable in our copy) says the PSD-95/SAPAP/Shank complex interfaces with the actin cytoskeleton at a deeper layer of the PSD. It does not say that actin is largely excluded from the PSD core or call the deeper layer the pallium. (LLM, conf=0.86)
Experimental — accuracy not yet measuredActin is largely excluded from the core of the PSD, and evidence suggests that, at least for the first hour, the changes in spine size are not accompanied by changes in the size of the PSD.
“Actin is largely excluded from the core of the PSD (66, 322), and evidence suggests that, at least for the first hour, the changes in spine size are not accompanied by changes in the size of the PSD (56).”
From Synaptic memory and CaMKII (2023) · cites this paper as [322]
The Introduction describes the PSD as containing cytoskeletal components, but does not say whether actin is excluded from its core. The Results measure spine head width, not PSD size or changes during the first hour. Searches for both points found no passage in our copy that addresses them. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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Cites
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“Actin is largely excluded from the core of the PSD (66, 322), and evidence suggests that, at least for the fi rst hour, the changes in spine size are not accompanied by changes in the size of the PSD (56).”
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- Authors
- Zhu, J., Zhou, Q., Shang, Y., Li, H., Peng, M., Ke, X., Weng, Z., Zhang, R., Huang, X., Li, S. S. C., Feng, G., Lu, Y., & Zhang, M.
- Affiliations
- Chinese Academy of Sciences (CN)
- Hong Kong University of Science and Technology (HK)
- Huazhong University of Science and Technology (CN)
- Western University (CA)
- Broad Institute (US)
- Corresponding author
- Zhang, Mingjie
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 21
- Issue
- 13
- Pages
- 3781-3793
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2779457463
- Cited by
- 68
- References
- 10
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 5 · 2023: 9 · 2022: 9 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 6
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Natural Science Foundation of China (31770779, 31470733, U1532121)
- Shanghai Municipal Science and Technology Commission, China (14YF1406700)
- SA-SIBS
- RGC of Hong Kong (16103614, 16149516, AoE-M09-12, C6009-15G)
- Minister of Science and Technology of China (2014CB910204)
- 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
- shank, PSD-95, MAGUK proteins, synaptic targeting, synaptogenesis, postsynaptic density, guanylate kinase, intellectual disability, peptide inhibitors, synapse maturation, synaptic plasticity
- MeSH terms
- SAP90-PSD95 Associated Proteins, Disks Large Homolog 4 Protein, Amino Acid Sequence, Animals, Humans, Intellectual Disability, Mice, Inbred C57BL, Models, Molecular, Mutation, Peptides, Phosphorylation, Protein Binding, Synapses, Dendritic Spines, Rats, Neurogenesis
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