Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA; Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA.
Cell Rep. 2019 Dec 3;29(10):2944-2952.e5. doi: 10.1016/j.celrep.2019.10.115.
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.
RhoGEFs Kalirin-7 和 Trio 是突触可塑性的调节因子，其失调与一系列神经发育和神经退行性疾病有关。尽管研究已经表明 Kalirin 和 Trio 都与某些疾病有关，例如tau 病，但它们在与其他疾病的关联方面存在显著差异。使用无偏蛋白质组学，我们鉴定了 Kalirin-7 和 Trio 的相互作用组，以确定与它们各自功能相关的独特蛋白质相互作用网络，并揭示了与特定 RhoGEF 优先相互作用的蛋白质组。相比之下，我们发现 Trio 与多种轴突导向和突触前复合物相互作用，而 Kalirin-7 则与几种突触粘附分子相互作用。具体而言，我们表明 Kalirin-7 是细胞粘附分子 neuroligin-1 (NLGN1) 的相互作用蛋白，并且 NLGN1 依赖性突触功能通过 Kalirin-7 以相互作用依赖的方式进行介导。我们的数据不仅揭示了两种重要疾病相关蛋白的相互作用组，还提供了 NLGN1 功能的细胞内效应子。
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