Li Jing, Wilkinson Brent, Clementel Veronica A, Hou Junjie, O'Dell Thomas J, Coba Marcelo P
Zilkha Neurogenetic Institute, Los Angeles, CA, 90089, USA.
National Laboratory of Bio-Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Sci Signal. 2016 Aug 9;9(440):rs8. doi: 10.1126/scisignal.aaf6716.
The postsynaptic site of neurons is composed of more than 1500 proteins arranged in protein-protein interaction complexes, the composition of which is modulated by protein phosphorylation through the actions of complex signaling networks. Components of these networks function as key regulators of synaptic plasticity, in particular hippocampal long-term potentiation (LTP). The postsynaptic density (PSD) is a complex multicomponent structure that includes receptors, enzymes, scaffold proteins, and structural proteins. We triggered LTP in the mouse hippocampus CA1 region and then performed large-scale analyses to identify phosphorylation-mediated events in the PSD and changes in the protein-protein interactome of the PSD that were associated with LTP induction. Our data indicated LTP-induced reorganization of the PSD. The dynamic reorganization of the PSD links glutamate receptor signaling to kinases (writers) and phosphatases (erasers), as well as the target proteins that are modulated by protein phosphorylation and the proteins that recognize the phosphorylation status of their binding partners (readers). Protein phosphorylation and protein interaction networks converged at highly connected nodes within the PSD network. Furthermore, the LTP-regulated phosphoproteins, which included the scaffold proteins Shank3, Syngap1, Dlgap1, and Dlg4, represented the "PSD risk" for schizophrenia and autism spectrum disorder, such that without these proteins in the analysis, the association with the PSD and these two psychiatric diseases was not present. These data are a rich resource for future studies of LTP and suggest that the PSD holds the keys to understanding the molecular events that contribute to complex neurological disorders that affect synaptic plasticity.
神经元的突触后位点由1500多种蛋白质组成，这些蛋白质排列成蛋白质 - 蛋白质相互作用复合体，其组成通过复杂信号网络的作用由蛋白质磷酸化调节。这些网络的组成部分作为突触可塑性的关键调节因子，特别是海马体长期增强（LTP）。突触后致密区（PSD）是一种复杂的多组分结构，包括受体、酶、支架蛋白和结构蛋白。我们在小鼠海马体CA1区触发LTP，然后进行大规模分析，以确定PSD中磷酸化介导的事件以及与LTP诱导相关的PSD蛋白质 - 蛋白质相互作用组的变化。我们的数据表明LTP诱导了PSD的重组。PSD的动态重组将谷氨酸受体信号传导与激酶（写入器）和磷酸酶（擦除器）联系起来，以及由蛋白质磷酸化调节的靶蛋白和识别其结合伙伴磷酸化状态的蛋白质（读取器）。蛋白质磷酸化和蛋白质相互作用网络在PSD网络内高度连接的节点处汇聚。此外，受LTP调节的磷蛋白，包括支架蛋白Shank3、Syngap1、Dlgap1和Dlg4，代表了精神分裂症和自闭症谱系障碍的“PSD风险”，因此在分析中没有这些蛋白质时，与PSD和这两种精神疾病的关联就不存在。这些数据为未来LTP研究提供了丰富的资源，并表明PSD是理解导致影响突触可塑性的复杂神经疾病的分子事件的关键。
