Molecular mechanisms of the synaptic organizer alpha-neurexin

突触组织者α-neurexin的分子机制

• 批准号: 8339687
• 负责人: Gabrielle Rudenko
• 金额: $ 38.33万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8339687
• 关键词: Adhesions; Amino Acids; Architecture; Autistic Disorder; Behavioral; Binding; Binding Proteins; Binding Sites; Biochemical; Biological; Biological Process; Cell Adhesion Molecules; Cells; Characteristics; Communication; Complex; Consensus; Data; Disease; Drug Delivery Systems; Dystroglycan; Extracellular Domain; Family; Goals; Health; Integral Membrane Protein; Knowledge; Laboratories; Leucine-Rich Repeat; Ligands; Maintenance; Mental Retardation; Mental disorders; Methods; Mission; Modeling; Molecular; Molecular Abnormality; National Institute of Mental Health; Neurons; Outcome; Pathology; Pathway interactions; Pharmaceutical Preparations; Plastics; Property; Proteins; Proteomics; Public Health; RNA Splicing; Recruitment Activity; Research; Schizophrenia; Specificity; Stretching; Surface; Synapses; Synaptic Cleft; Synaptic Transmission; Techniques; Testing; Work; autism spectrum disorder; base; design; extracellular; flexibility; innovation; molecular assembly/self assembly; neurexophilin; neuropsychiatry; novel; protein complex; receptor; scaffold; small molecule; synaptic function; synaptogenesis; treatment strategy

DESCRIPTION (provided by applicant): Alpha-neurexins and many of the proteins they recruit are implicated in neuropsychiatric diseases including schizophrenia, autism spectrum disorder, and mental retardation - diseases that are in desperate need of better medications. Alpha-neurexins are synaptic organizers involved in neuronal communication, and are diversified though small stretches of amino acids called splice inserts. It is not known how alpha-neurexins utilize their molecular features to bind a diverse array of partners in the synaptic cleft includin neuroligins, leucine rich repeat transmembrane proteins (LRRTMs), neurexophilins, GABAA-receptors, and likely as yet unidentified proteins as well. It is important to understand the molecular mechanisms that enable alpha-neurexins to bind their diverse partners, because when these interactions are disrupted, fundamental biological processes are altered that are thought to contribute to the pathology of many severe mental disorders. The long term goal of our laboratory is to understand on a molecular level how proteins in the synaptic cleft integrate into highly organized protein interaction networks that form and maintain functional synapses. The objective of this particular application is to reveal how the family of alpha-neurexins works as synaptic organizers to assemble diverse proteins into distinct protein complexes at different synapses. The central hypothesis is that alpha-neurexins exploit their unique molecular features to generate a portfolio of distinct and plastic binding sites. Firstly, we hypothesize that alpha-neurexins use their characteristic nine domain extracellular region to create a molecular scaffold that spatially organizes proteins in the synaptic cleft. Secondly, we hypothesize that alpha-neurexins generate distinct binding surfaces using splice insert-dependent and splice insert-independent molecular frameworks. This hypothesis is supported by strong preliminary data presented by the applicant entailing structural studies, proteomic data, biophysical data using a new method to study molecular interactions, as well as biochemical and cell-based techniques. The hypothesis will be tested by pursuing three specific aims: 1) delineate the molecular features that enable protein partners to bind in a splice insert-dependent, alpha-neurexin-dependent manner; 2) delineate the molecular features that enable protein partners to bind in a splice insert-independent, alpha-neurexin- dependent manner; and finally 3) establish the binding mode of a new partner that we have identified specific for alpha-neurexins. The rationale for this proposal is that the results will reveal how alpha-neurexins organize different molecular assemblies in the synaptic cleft which take part in biological processes involved in severe neuropsychiatric diseases. The proposal is innovative because it provides a starting point to design strategies to manipulate alpha-neurexin interactions in the synaptic cleft using small molecule compounds or biologics. This information is very significant because it could reveal completely new drug targets to reverse pathological effects of neuropsychiatric disorders and create completely new strategies to treat these devastating disorders. PUBLIC HEALTH RELEVANCE: Alpha-neurexins, a large family of synaptic organizers, have recently been implicated in neuropsychiatric diseases, including schizophrenia and autism spectrum disorder. There is growing consensus that alpha- neurexins, but also many of their protein partners, contribute to biological pathways that are disrupted in many mental disorders. The proposed research will reveal the molecular frameworks used by alpha- neurexins to recruit many different proteins into different multi-protein complexes in the synaptic cleft with different functions. This research is relevant to public health and the mission of NIMH, because detailed molecular knowledge of alpha-neurexin:protein partner interactions could provide new strategies to manipulate neurexin interactions within the synaptic cleft, in order to ameliorate behavioral deficits associated with neuropsychiatric disorders.

描述（由申请人提供）：他们招募的α-毒素及其许多蛋白质与神经精神疾病有关，包括精神分裂症，自闭症谱系障碍和智力低下 - 迫切需要对更好的药物的疾病。 α-系素是参与神经元通信的突触组织者，并具有多样化的氨基酸，称为剪接插入物。尚不清楚α-素毒素如何利用其分子特征来结合突触裂缝中的各种伴侣，包括神经素，富含亮氨酸的重复跨膜蛋白（LRRRTMS），神经毒素，神经毒素，GABAA-GABAA-epectors，gabaa-pectoptors，以及可能尚未确定的蛋白质。重要的是要了解能够使α-系素的分子机制约束其多样化的伴侣，因为当这些相互作用受到破坏时，基本的生物学过程被改变，这些过程被认为有助于许多严重的精神疾病的病理。我们实验室的长期目标是在分子水平上了解突触裂缝中的蛋白如何整合到高度有组织的蛋白质相互作用网络中，从而形成和维持功能突触。该特定应用的目的是揭示α-纽雷素家族如何充当突触组织者，以将多种蛋白质组装成不同突触处的不同蛋白质复合物。中心假设是α-系蛋白利用其独特的分子特征来产生不同的塑料结合位点的投资组合。首先，我们假设α-海龙素使用其特征性的九个结构域外细胞外区域来创建一个分子支架，该分子支架在空间上组织了突触裂缝中的蛋白质。其次，我们假设使用剪接插入依赖性和剪接插入插入无关的分子框架，α-素蛋白会产生独特的结合表面。申请人提供的结构研究，蛋白质组学数据，生物物理数据使用新方法研究分子相互作用以及生化和基于细胞的技术。该假设将通过追求三个特定目的来检验：1）描述使蛋白质伴侣能够以剪接插入依赖性的，α-抑制依赖性方式结合的分子特征； 2）描述使蛋白质伴侣能够以剪接插入插入独立的，α-平线素依赖性方式结合的分子特征；最后3）建立了我们已确定针对α-素素特异性的新合作伙伴的结合模式。该提议的理由是，结果将揭示α-静脉素如何在突触裂隙中组织不同的分子组件，这参与了严重神经精神疾病的生物学过程。该提案具有创新性，因为它提供了设计策略的起点，以使用小分子化合物或生物制剂来操纵突触裂隙中的α-Neurexin相互作用。这些信息非常重要，因为它可以揭示全新的药物靶标，以逆转神经精神疾病的病理影响，并创建全新的策略来治疗这些毁灭性疾病。 公共卫生相关性：大型突触组织者家族α-素毒素最近与神经精神疾病有关，包括精神分裂症和自闭症谱系障碍。越来越多的共识表明，字母神经毒素，但其许多蛋白质伴侣也有助于在许多精神疾病中破坏的生物学途径。拟议的研究将揭示字母神经毒素使用的分子框架将许多不同的蛋白质募集到突触中的不同多蛋白质复合物中 功能。这项研究与公共卫生和NIMH的使命相关，因为详细的对α-系菌素的分子知识：蛋白质伴侣的相互作用可以提供新的策略来操纵突触裂隙中的神经毒素相互作用，以减轻与神经性精神疾病相关的行为缺陷。