LaConte Leslie E W, Chavan Vrushali, Liang Chen, Willis Jeffery, Schönhense Eva-Maria, Schoch Susanne, Mukherjee Konark
Virginia Tech Carilion Research Institute, 2 Riverside Cir., Roanoke, VA, 24016, USA.
Institute of Neuropathology, Sigmund Freud Strasse 25, 53105, Bonn, Germany.
Cell Mol Life Sci. 2016 Sep;73(18):3599-621. doi: 10.1007/s00018-016-2183-4. Epub 2016 Mar 25.
CASK, a MAGUK family protein, is an essential protein present in the presynaptic compartment. CASK's cellular role is unknown, but it interacts with multiple proteins important for synapse formation and function, including neurexin, liprin-α, and Mint1. CASK phosphorylates neurexin in a divalent ion-sensitive manner, although the functional relevance of this activity is unclear. Here we find that liprin-α and Mint1 compete for direct binding to CASK, but neurexin1β eliminates this competition, and all four proteins form a complex. We describe a novel mode of interaction between liprin-α and CASK when CASK is bound to neurexin1β. We show that CASK phosphorylates neurexin, modulating the interaction of liprin-α with the CASK-neurexin1β-Mint1 complex. Thus, CASK creates a regulatory and structural link between the presynaptic adhesion molecule neurexin and active zone organizer, liprin-α. In neuronal culture, CASK appears to regulate the stability of neurexin by linking it with this multi-protein presynaptic active zone complex.
CASK是一种膜相关鸟苷酸激酶（MAGUK）家族蛋白，是存在于突触前区室的一种必需蛋白。CASK的细胞功能尚不清楚，但它与多种对突触形成和功能重要的蛋白质相互作用，包括神经连接蛋白、liprin-α和Mint1。CASK以二价离子敏感的方式磷酸化神经连接蛋白，尽管这种活性的功能相关性尚不清楚。在这里，我们发现liprin-α和Mint1竞争与CASK的直接结合，但神经连接蛋白1β消除了这种竞争，并且这四种蛋白质形成了一个复合物。我们描述了当CASK与神经连接蛋白1β结合时，liprin-α与CASK之间一种新的相互作用模式。我们表明，CASK磷酸化神经连接蛋白，调节liprin-α与CASK-神经连接蛋白1β-Mint1复合物的相互作用。因此，CASK在突触前粘附分子神经连接蛋白和活性区组织者liprin-α之间建立了一种调节和结构联系。在神经元培养中，CASK似乎通过将神经连接蛋白与这种多蛋白突触前活性区复合物联系起来，从而调节神经连接蛋白的稳定性。
