Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action.
Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action.
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DOI：
10.1016/j.celrep.2019.10.115
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发表时间：
2019-12-03
期刊：
影响因子：
8.8
通讯作者：
Roche, Katherine W.
中科院分区：
文献类型：
--
作者：
Paskus, Jeremiah D.;Tian, Chen;Fingleton, Erin;Shen, Christine;Chen, Xiaobing;Li, Yan;Myers, Samuel A.;Badger, John D.;Bemben, Michael A.;Herring, Bruce E.;Roche, Katherine W.
RhoGEF Kalirin-7和Trio是突触可塑性的调节剂，它们的失调与一系列神经发育和神经退行性疾病相关。虽然研究表明Kalirin和Trio都与某些疾病有关，如Tau蛋白病，但它们与其他疾病的相关性显着不同。使用无偏蛋白质组学，我们确定了Kalirin-7和Trio的相互作用组，以确定与其各自功能相关的不同蛋白质关联网络，并揭示了优先与特定RhoGEF相互作用的蛋白质组。相比之下，我们发现Trio与一系列轴突导向和突触前复合物相互作用，而Kalirin-7与几种突触粘附分子相互作用。具体而言，我们显示Kalirin-7是细胞粘附分子神经连接素-1（NLGN 1）的相互作用物，并且NLGN 1依赖性突触功能以相互作用依赖的方式通过Kalirin-7介导。我们的数据不仅揭示了两种重要的疾病相关蛋白的相互作用，而且还提供了NLGN 1功能的细胞内效应子。Paskus等人使用定量蛋白质组学来确定疾病相关蛋白Kalirin-7和Trio的突触相互作用组，将Kalirin-7鉴定为NLGN 1的相互作用物。对这种相互作用的研究揭示了Kalirin-7作为NLGN 1功能获得的主要细胞内效应物。
The RhoGEFs Kalirin-7 and Trio are regulators of synaptic plasticity, and their dysregulation is associated with a range of neurodevelopmental and neurodegenerative disorders. Although studies have implicated both Kalirin and Trio in certain diseases, such as tauopathies, they remarkably differ in their association with other disorders. Using unbiased proteomics, we identified interactomes of Kalirin-7 and Trio to ascertain distinct protein association networks associated with their respective function and revealed groups of proteins that preferentially interact with a particular RhoGEF. In comparison, we find Trio interacts with a range of axon guidance and presynaptic complexes, whereas Kalirin-7 associates with several synaptic adhesion molecules. Specifically, we show Kalirin-7 is an interactor of the cell adhesion molecule neuroligin-1 (NLGN1), and NLGN1-dependent synaptic function is mediated through Kalirin-7 in an interaction-dependent manner. Our data reveal not only the interactomes of two important disease-related proteins, but also provide an intracellular effector of NLGN1 function. Paskus et al. use quantitative proteomics to determine the synaptic interactomes of the disease-associated proteins Kalirin-7 and Trio, identifying Kalirin-7 as an interactor of NLGN1. Investigation of this interaction unveils Kalirin-7 as a primary intracellular effector of NLGN1 gain of function.
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