Neurexins: synaptic building blocks

神经毒素：突触构件

• 批准号: 7871043
• 负责人: Gabrielle Rudenko
• 金额: $ 31.3万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871043
• 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; 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; Location; Memory; Metal Binding Site; Modeling; Molecular; Molecular Profiling; Nature; Neurologic; Neurons; Peptide Sequence Determination; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Property; Protein Isoforms; Proteins; Proteolysis; Psychiatric therapeutic procedure; RNA Splicing; Regulation; Role; Site; Site-Directed Mutagenesis; Specificity; Structure; Surface; Synapses; Synaptic Membranes; Synaptic plasticity; 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; treatment strategy

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）：神经毒素在突触中起着重要作用，促进神经元之间的粘附和交流。通过称为替代剪接的过程生成2000多个神经素同工型。工作模型：神经毒素被认为是确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，而神经蛋白仅存在于突触前膜上。晶体学表明，特定表面是通过在神经LNS/LG结构域（细胞外区域的模块）中的剪接来调节的。我们的长期目标是在原子层面上了解神经元如何帮助神经元在形成高度特定的神经回路时彼此认识，粘附和交流。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素工作。首先，我们假设Neurexin LNS/LG结构域包含一个由两个结构特征调节的配体结合表面1）替代剪接和2）Ca2+占用金属结合位点。其次，我们假设LNS/LG结构域在空间中安排，以相互组织变异区域（通过剪接产生）相互相互构想，从而增加了额外的调节水平。具体目的：（1）将神经毒素LNS/LG结构域中的配体结合表面描述（2）评估Ca2+结合位点在Neurexin LNS/LG结构域中的相关性作为配体结合的分子开关。 （3）揭示替代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：神经毒素使用其原子特征来识别和绑定不同的伴侣。 Neuroligin和Alpha-dystroglycan（仅结合特定神经胶质剪接变体）的两个伴侣与自闭症和liss脑有关。然而，神经毒素可能通过其突触位置和本质性质，影响人类过程中的更广泛的过程，具有突触基础的过程，包括记忆，学习，吸毒行为和某些神经系统疾病的基础机制及其精神病治疗。了解神经毒素如何在分子水平上有助于突触功能，最终可以指导开发脑部疾病治疗的新策略。