Li Jing, Zhang Wangshu, Yang Hui, Howrigan Daniel P, Wilkinson Brent, Souaiaia Tade, Evgrafov Oleg V, Genovese Giulio, Clementel Veronica A, Tudor Jennifer C, Abel Ted, Knowles James A, Neale Benjamin M, Wang Kai, Sun Fengzhu, Coba Marcelo P
Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, USA.
Nat Neurosci. 2017 Aug;20(8):1150-1161. doi: 10.1038/nn.4594. Epub 2017 Jun 26.
The postsynaptic density (PSD) contains a collection of scaffold proteins used for assembling synaptic signaling complexes. However, it is not known how the core-scaffold machinery associates in protein-interaction networks or how proteins encoded by genes involved in complex brain disorders are distributed through spatiotemporal protein complexes. Here using immunopurification, proteomics and bioinformatics, we isolated 2,876 proteins across 41 in vivo interactomes and determined their protein domain composition, correlation to gene expression levels and developmental integration to the PSD. We defined clusters for enrichment of schizophrenia, autism spectrum disorders, developmental delay and intellectual disability risk factors at embryonic day 14 and adult PSD in mice. Mutations in highly connected nodes alter protein-protein interactions modulating macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform, Synaptic Protein/Pathways Resource (SyPPRes), enabling the prioritization of disease risk factors and their placement within synaptic protein interaction networks.
突触后致密区（PSD）包含一组用于组装突触信号复合物的支架蛋白。然而，目前尚不清楚核心支架机制在蛋白质相互作用网络中是如何关联的，也不清楚复杂脑部疾病相关基因所编码的蛋白质是如何通过时空蛋白质复合物分布的。在这里，我们利用免疫纯化、蛋白质组学和生物信息学技术，在41个体内相互作用组中分离出2876种蛋白质，并确定了它们的蛋白质结构域组成、与基因表达水平的相关性以及与PSD的发育整合情况。我们定义了一些簇，用于富集小鼠胚胎第14天和成年PSD中精神分裂症、自闭症谱系障碍、发育迟缓及智力残疾的风险因素。高度连接节点中的突变会改变蛋白质-蛋白质相互作用，从而调节富含疾病风险候选物的大分子复合物。这些结果被整合到一个软件平台——突触蛋白/信号通路资源（SyPPRes）中，从而能够对疾病风险因素进行优先级排序，并将它们定位在突触蛋白质相互作用网络中。
