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

• Published in: Cell reports (Cambridge) 2017-12, Vol.21 (13), p.3781-3793
• Main Authors: Zhu, Jinwei, Zhou, Qingqing, Shang, Yuan, Li, Hao, Peng, Mengjuan, Ke, Xiao, Weng, Zhuangfeng, Zhang, Rongguang, Huang, Xuhui, Li, Shawn S.C., Feng, Guoping, Lu, Youming, Zhang, Mingjie
• Format: Article
• Language: English
• Subjects: GK domain; MAGUK; postsynaptic density; PSD-95; SAPAP; synaptic plasticity; synaptic scaffold proteins; synaptogenesis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.11.107

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. [Display omitted] •Phosphorylation-dependent complex formation revealed by the SAPAP/PSD-95 structure•Phosphorylation is required for synaptic targeting and maturation functions of SAPAPs•A potent non-phosphorylated PSD-95 GK inhibitory peptide is developed•This PSD-95 inhibitory peptide weakens excitatory synaptic strength 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.