Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs.
Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs.
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DOI：
10.1016/j.celrep.2017.11.107
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发表时间：
2017-12
期刊：
影响因子：
8.8
通讯作者：
Jinwei Zhu;Qingqing Zhou;Y. Shang;Hao Li;Mengjuan Peng;Xiao Ke;Z. Weng;Rong-guang Zhang;
中科院分区：
文献类型：
--
作者：
Jinwei Zhu;Qingqing Zhou;Y. Shang;Hao Li;Mengjuan Peng;Xiao Ke;Z. Weng;Rong-guang Zhang;
PSD-95/SAPAP/Shank复合物在协调突触后密度（PSD）的形成和可塑性中作为主要支架发挥作用。我们以前证明，精致的特异性SAPAP/柄的相互作用是至关重要的柄突触靶向和柄介导的突触发生。在这里，我们表明，PSD-95/SAPAP相互作用，SAPAP突触靶向，和SAPAP介导的突触需要磷酸化的N-末端重复序列的SAPAPs。PSD-95鸟苷酸激酶（GK）与磷酸化-SAPAP重复肽复合物的原子结构，以及生物化学研究，揭示了磷酸化依赖的PSD-95/SAPAP相互作用的分子机制，并且还解释了在智力残疾患者中发现的PSD-95突变。在结构数据的指导下，我们开发了有效的非磷酸化GK抑制肽，能够阻断PSD-95/SAPAP相互作用并干扰PSD-95/SAPAP介导的突触成熟和强度。这些肽段是可遗传编码的，可用于研究PSD-95/SAPAP相互作用的体内功能。
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 interactionin vivo.