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Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs.

Zhu J, Zhou Q, Shang Y, Li H, Peng M, Ke X, Weng Z, Zhang R, Huang X, Li SSC, Feng G, Lu Y, Zhang M
Cell Rep 21 3781-3793 (2017)
Cited: 25 times
EuropePMC logo PMID: 29281827

Abstract

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.

Articles - 5ypr mentioned but not cited (4)

  1. Characterizing the Binding Sites for GK Domain of DLG1 and DLG4 via Molecular Dynamics Simulation. Li H, Chen Q, Shan C, Guo C, Yang X, Chen Y, Zhu J, Ouyang Q. Front Mol Biosci 7 1 (2020)
  2. Application of per-Residue Energy Decomposition to Design Peptide Inhibitors of PSD95 GK Domain. Tian M, Li H, Yan X, Gu J, Zheng P, Luo S, Zhangsun D, Chen Q, Ouyang Q. Front Mol Biosci 9 848353 (2022)
  3. Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density. Shen Z, Sun D, Savastano A, Varga SJ, Cima-Omori MS, Becker S, Honigmann A, Zweckstetter M. Nat Commun 14 6839 (2023)
  4. Phosphorylation-dependent recognition of diverse protein targets by the cryptic GK domain of MAGI MAGUKs. Zhang M, Cao A, Lin L, Chen Y, Shang Y, Wang C, Zhang M, Zhu J. Sci Adv 9 eadf3295 (2023)


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  1. Phase separation at the synapse. Chen X, Wu X, Wu H, Zhang M. Nat Neurosci 23 301-310 (2020)
  2. Post-translational modifications in liquid-liquid phase separation: a comprehensive review. Li J, Zhang M, Ma W, Yang B, Lu H, Zhou F, Zhang L. Mol Biomed 3 13 (2022)
  3. The Emerging Role of Mechanics in Synapse Formation and Plasticity. Kilinc D. Front Cell Neurosci 12 483 (2018)
  4. Synaptic memory and CaMKII. Nicoll RA, Schulman H. Physiol Rev 103 2877-2925 (2023)
  5. The Role of Amyloid-Beta and Tau in the Early Pathogenesis of Alzheimer's Disease. Yin X, Qiu Y, Zhao C, Zhou Z, Bao J, Qian W. Med Sci Monit 27 e933084 (2021)
  6. Molecular physiology of Arc/Arg3.1: The oligomeric state hypothesis of synaptic plasticity. Eriksen MS, Bramham CR. Acta Physiol (Oxf) 236 e13886 (2022)
  7. Orchestrating serine/threonine phosphorylation and elucidating downstream effects by short linear motifs. Kliche J, Ivarsson Y. Biochem J 479 1-22 (2022)
  8. SAPAP Scaffold Proteins: From Synaptic Function to Neuropsychiatric Disorders. Bai Y, Wang H, Li C. Cells 11 3815 (2022)
  9. Inhibitory postsynaptic density from the lens of phase separation. Bai G, Zhang M. Oxf Open Neurosci 1 kvac003 (2022)
  10. The Neurobiological Underpinnings of Obsessive-Compulsive Symptoms in Psychosis, Translational Issues for Treatment-Resistant Schizophrenia. Vellucci L, Ciccarelli M, Buonaguro EF, Fornaro M, D'Urso G, De Simone G, Iasevoli F, Barone A, de Bartolomeis A. Biomolecules 13 1220 (2023)

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