Araç Demet, Boucard Antony A, Ozkan Engin, Strop Pavel, Newell Evan, Südhof Thomas C, Brunger Axel T
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Neuron. 2007 Dec 20;56(6):992-1003. doi: 10.1016/j.neuron.2007.12.002.
Neurexins and neuroligins provide trans-synaptic connectivity by the Ca2+-dependent interaction of their alternatively spliced extracellular domains. Neuroligins specify synapses in an activity-dependent manner, presumably by binding to neurexins. Here, we present the crystal structures of neuroligin-1 in isolation and in complex with neurexin-1 beta. Neuroligin-1 forms a constitutive dimer, and two neurexin-1 beta monomers bind to two identical surfaces on the opposite faces of the neuroligin-1 dimer to form a heterotetramer. The neuroligin-1/neurexin-1 beta complex exhibits a nanomolar affinity and includes a large binding interface that contains bound Ca2+. Alternatively spliced sites in neurexin-1 beta and in neuroligin-1 are positioned nearby the binding interface, explaining how they regulate the interaction. Structure-based mutations of neuroligin-1 at the interface disrupt binding to neurexin-1 beta, but not the folding of neuroligin-1 and confirm the validity of the binding interface of the neuroligin-1/neurexin-1 beta complex. Our results provide molecular insights for understanding the role of cell-adhesion proteins in synapse function.
神经连接蛋白和神经配体通过其可变剪接的细胞外结构域的钙离子依赖性相互作用提供跨突触连接。神经配体以活动依赖的方式确定突触，可能是通过与神经连接蛋白结合来实现。在此，我们展示了单独的神经配体-1以及与神经连接蛋白-1β形成复合物时的晶体结构。神经配体-1形成一个组成型二聚体，两个神经连接蛋白-1β单体结合到神经配体-1二聚体相对面上的两个相同表面，形成一个异源四聚体。神经配体-1/神经连接蛋白-1β复合物表现出纳摩尔级亲和力，并且包括一个含有结合钙离子的大结合界面。神经连接蛋白-1β和神经配体-1中的可变剪接位点位于结合界面附近，解释了它们如何调节相互作用。基于结构在界面处对神经配体-1进行突变会破坏其与神经连接蛋白-1β的结合，但不影响神经配体-1的折叠，并证实了神经配体-1/神经连接蛋白-1β复合物结合界面的有效性。我们的结果为理解细胞粘附蛋白在突触功能中的作用提供了分子层面的见解。
