Neurexins: synaptic building blocks

描述（由申请人提供）：Neurexins在突触中发挥重要作用，促进神经元之间的粘附和通信。通过一种称为选择性剪接的过程，产生了2000多种神经素同工型。工作模型：神经素被认为是决定神经元的特异性因素：神经元相互作用，因为不同的剪接变体在时间和空间上表达，剪接变体结合不同的蛋白质伴侣，神经素只存在于突触前膜上。晶体学揭示了一个特定的表面是由神经蛋白LNS/LG结构域（细胞外区域的模块）的剪接调节的。我们的长期目标是在原子水平上理解神经素是如何帮助神经元在形成高度特定的神经回路时相互识别、粘附和交流的。假设：神经毒素在其三维结构中具有特定的特征，使它们能够作为特异性因子发挥作用。首先，我们假设neurexin LNS/LG结构域包含一个配体结合表面，该表面受两个结构特征的调节：1)选择性剪接和2)Ca2+占据金属结合位点。其次，我们假设LNS/LG结构域在空间中排列，以组织彼此之间的变异区域（通过剪接产生），从而增加了额外的调节水平。具体目的：(1)描述neurexin LNS/LG结构域的配体结合表面(2)评估neurexin LNS/LG结构域Ca2+结合位点作为配体结合的分子开关的相关性。(3)揭示选择性剪接如何改变配体结合表面的表位。(4)确定神经毒素细胞外区域的结构域排列。相关性：神经蛋白利用它们的原子特征来识别和结合不同的伴侣。神经胶质素和α -糖营养不良蛋白是两个只结合特定神经蛋白剪接变体的伴侣，它们与自闭症和缺脑症有关。然而，神经素很可能通过其突触位置和本质，影响人类更广泛的过程，这些过程以突触为基础，包括记忆、学习、药物成瘾行为和某些神经系统疾病及其精神治疗的潜在机制。了解神经生长素如何在分子水平上帮助突触功能，可能最终指导治疗脑部疾病的新策略的发展。

DESCRIPTION (provided by applicant): Neurexins play an important role at the synapse, promoting adhesion and communication between neurons. More than 2000 neurexin isoforms are generated through a process called alternative splicing. WORKING MODEL: Neurexins are thought to be specificity factors determining neuron:neuron interactions because different splice variants are temporally and spatially expressed, splice variants bind different protein partners, and neurexins are present only on the pre-synaptic membrane. Crystallography has revealed that a specific surface is modulated by splicing in neurexin LNS/LG domains (modules in the extracellular region). OUR LONG TERM GOAL is to understand on an atomic level how neurexins help neurons recognize, adhere and communicate with each other as they form highly specific neural circuits. HYPOTHESES: Neurexins have specific features in their three-dimensional structure that enable them to work as specificity factors. Firstly, we hypothesize that neurexin LNS/LG domains contain a ligand binding surface that is regulated by two structural features 1) alternative splicing and 2) occupancy of a metal binding site by Ca2+. Secondly, we hypothesize that LNS/LG domains are arranged in space to organize areas of variation (produced through splicing) with respect to each other, adding an additional level of regulation. SPECIFIC AIMS: (1) Delineate the ligand binding surface in neurexin LNS/LG domains (2) Assess the relevance of the Ca2+ binding site in neurexin LNS/LG domains as a molecular switch for ligand binding. (3) Reveal how alternative splicing changes epitopes of the ligand binding surface. (4) Determine the domain arrangement in the extracellular region of neurexins. RELEVANCE: Neurexins use their atomic features to recognize and bind different partners. Neuroligin and alpha-dystroglycan, two partners that bind only specific neurexin splice variants, are associated with autism and lissencephalies. It is likely however that neurexins, through their synaptic location and essential nature, impact a much broader range of processes in humans, processes with a synaptic basis including memory, learning, drug addictive behavior and mechanisms underlying certain neurological illnesses and their psychiatric treatments. Understanding how neurexins aid synaptic function on a molecular level may ultimately guide the development of new strategies for the treatments of brain illnesses.