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）：α -神经素和它们募集的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迟钝——这些疾病迫切需要更好的药物治疗。α -神经素是参与神经元交流的突触组织者，通过被称为剪接插入的氨基酸的小片段而多样化。目前尚不清楚α -神经毒素如何利用其分子特征在突触间隙中结合多种伙伴，包括神经素、富含亮氨酸的重复跨膜蛋白（LRRTMs）、嗜神经素、gabaa受体以及可能尚未识别的蛋白质。了解使α -神经素结合其不同伙伴的分子机制是很重要的，因为当这些相互作用被破坏时，基本的生物学过程就会改变，这被认为是导致许多严重精神障碍病理的原因。我们实验室的长期目标是在分子水平上理解突触间隙中的蛋白质如何整合到形成和维持功能性突触的高度有组织的蛋白质相互作用网络中。这个特殊应用的目的是揭示α -神经毒素家族如何作为突触组织者将不同的蛋白质组装成不同的蛋白质复合物在不同的突触。核心假设是，α -神经毒素利用其独特的分子特征来产生一系列独特的、可塑的结合位点。首先，我们假设α -神经毒素利用其特有的九结构域细胞外区域来创建一个分子支架，在突触间隙中空间组织蛋白质。其次，我们假设α -神经素使用剪接插入依赖和剪接插入独立的分子框架产生不同的结合表面。这一假设得到了申请人提供的强有力的初步数据的支持，这些数据包括结构研究、蛋白质组学数据、使用新方法研究分子相互作用的生物物理数据，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标来验证：1)描述使蛋白质伴侣能够以剪接插入依赖、α -神经素依赖的方式结合的分子特征；2)描述使蛋白质伴侣以剪接插入不依赖、α -神经毒素依赖的方式结合的分子特征；最后3)建立一个新的合作伙伴的结合模式，我们已经确定了特异性的α -神经毒素。这一建议的基本原理是，结果将揭示α -神经毒素如何在突触间隙中组织不同的分子组装，这些分子组装参与了严重神经精神疾病的生物过程。这一建议具有创新性，因为它为设计利用小分子化合物或生物制剂在突触间隙中操纵α -神经素相互作用的策略提供了一个起点。这一信息非常重要，因为它可以揭示全新的药物靶点，以逆转神经精神疾病的病理影响，并创造全新的策略来治疗这些毁灭性的疾病。