Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs
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Author(s)
Zhu, Jinwei
Zhou, Qingqing
Shang, Yuan
Li, Hao
Peng, Mengjuan
Ke, Xiao
Weng, Zhuangfeng
Zhang, Rongguang
Huang, Xuhui
Li, Shawn S.C.
Date Issued
December 2017
Journal
Cell Reports
Publisher
Elsevier
Citation
Zhu, Jinwei et al. “Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs.” Cell Reports 21, 13 (December 2017): 3781–3793 © 2017 The Author(s)
Version
Final published version
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. Using structural biology, cell biology, and electrophysiology approaches, Zhu et al. demonstrate that phosphorylation of the N-terminal repeating sequences of SAPAPs is required for the SAPAP/PSD-95 complex formation and SAPAP's synaptic targeting and maturation functions. They also developed a potent non-phosphorylated PSD-95 GK inhibitory peptide that can effectively disrupt the SAPAP/PSD-95 complex formation and thus inhibit excitatory synaptic activities. Keywords: GK domain; PSD-95; SAPAP; MAGUK; postsynaptic density; synaptic scaffold proteins; synaptogenesis; synaptic plasticity
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
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Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
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DOI of Published Version
https://doi.org/10.1016/J.CELREP.2017.11.107
