Neurexins: synaptic building blocks

神经毒素：突触构件

• 批准号: 7215204
• 负责人: Gabrielle Rudenko
• 金额: $ 25.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215204
• 关键词: Addictive Behavior; Adhesions; Affinity; Alternative Splicing; Amino Acid Sequence; Area; Autistic Disorder; Binding; Binding Sites; Brain; Calorimetry; Cell Surface Proteins; Cell surface; Chromosome Pairing; Communication; Complex; Crystallography; Defect; Development; Dystroglycan; Epitopes; Equilibrium; Excitatory Synapse; Extracellular Domain; Family; Fluorescence; Goals; Human; In Vitro; Lead; Learning; Length; Ligand Binding; Ligands; Link; Localized; Location; Memory; Metal Binding Site; Modeling; Molecular; Molecular Profiling; Nature; Neurologic; Neurons; Numbers; Peptide Sequence Determination; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Property; Protein Isoforms; Proteins; Proteolysis; Psychiatric therapeutic procedure; RNA Splicing; Range; Regulation; Role; Site; Site-Directed Mutagenesis; Specificity; Structure; Surface; Synapses; Synaptic Membranes; Synaptic plasticity; Thinking; Time; Titrations; Variant; Work; X-Ray Crystallography; alpha Dystroglycan; analytical ultracentrifugation; base; brain malformation; congenital muscular dystrophy; design; extracellular; insight; neural circuit; neurotransmitter release; numb protein; synaptic function; three dimensional structure

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.

描述（由申请人提供）：神经毒素在突触中发挥重要作用，促进神经元之间的粘附和通讯。超过 2000 种神经素亚型是通过称为选择性剪接的过程产生的。工作模型：神经毒素被认为是决定神经元与神经元相互作用的特异性因素，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，并且神经毒素仅存在于突触前膜上。晶体学表明，特定表面是通过神经素 LNS/LG 结构域（细胞外区域的模块）中的剪接进行调节的。我们的长期目标是在原子水平上了解神经毒素如何帮助神经元在形成高度特异性的神经回路时识别、粘附和相互交流。假设：神经毒素的三维结构具有特定的特征，使其能够作为特异性因子发挥作用。首先，我们假设神经毒素 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），从而增加额外的调节水平。具体目标： (1) 描绘神经毒素 LNS/LG 结构域中的配体结合表面 (2) 评估神经毒素 LNS/LG 结构域中 Ca2+ 结合位点作为配体结合分子开关的相关性。 (3)揭示选择性剪接如何改变配体结合表面的表位。 (4)确定神经毒素胞外区的结构域排列。相关性：神经毒素利用其原子特征来识别和结合不同的伙伴。 Neuroligin 和 α-dystroglycan 是仅结合特定神经素剪接变体的两种伙伴，与自闭症和无脑畸形有关。然而，神经毒素通过其突触位置和本质性质，可能会影响人类更广泛的过程，这些过程具有突触基础，包括记忆、学习、药物成瘾行为以及某些神经系统疾病及其精神治疗的潜在机制。了解神经毒素如何在分子水平上帮助突触功能可能最终指导开发治疗脑部疾病的新策略。