Mapping glycan-dependent neurexin interactomes

映射聚糖依赖性神经毒素相互作用组

基本信息

批准号：
10426737
负责人：
Mia L Huang
金额：
$ 31.06万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10426737
关键词：
Architecture Binding Binding Proteins Biochemistry Biology Brain Calcium Catalogs Cell Adhesion Molecules Cell surface Cells Chemicals Cognition Disorders Communication Complex Comprehension Core Protein Data Defect Development Disease Engineering Enzyme-Linked Immunosorbent Assay Evaluation Event Exhibits Gilles de la Tourette syndrome Glycoconjugates Glycosaminoglycans Goals Heterogeneity Hippocampus (Brain)In Vitro Knowledge Lead Ligands Maintenance Maps Mass Spectrum Analysis Mediating Modification Mus Neurons Outcome Pattern Phase Plant Roots Polysaccharides Process Protein Glycosylation Protein Isoforms Protein Tyrosine Phosphatase Proteoglycan Proteomics Research Resolution Reverse engineering Schizophrenia Structure Structure-Activity Relationship Sulfate Synapses Techniques Technology Transact Transfection Work base design genetic approach genetic manipulation glycosylation human interactome innovation intercellular connection nervous system disorder pleiotrophin presynaptic neurons protein protein interaction protein structure relating to nervous system synaptic function targeted treatment tool

项目摘要

PROJECT SUMMARY Neurexin is an important cell adhesion molecule on pre-synaptic neurons that mediates important binding events to form synapses, the most fundamental unit of neuronal communication. Alterations in neurexin structure underlie many cognitive and neurological diseases. Our limited understanding of neurexin structure hampers our ability to develop targeted therapies to alleviate these disorders. Recent discoveries have found that neurexin is a glycoconjugate decorated with diverse glycosaminoglycan structures. These findings are exciting and prompt the requirement for a comprehensive and glycan-dependent understanding of neurexin structure-binding relationships. However, such studies are challenging, given the diversity and heterogeneity of glycosaminoglycans. Using an innovative proteoglycan editing platform rooted in chemical biology, we will fabricate defined and replete neurexin ectodomains and refine binding relationships with known binding partners (evaluation phase, Aim 1). Subsequently, we will apply these molecules to live primary neurons and display them in a de novo fashion on cell surfaces, such that we can use proximity tagging to capture their corresponding interactomes (discovery phase, Aim 2). These sophisticated materials will serve as important tools to define and evaluate neurexin ligands, and the overall outcome of this application will be a catalogue of neurexin interactomes defined by their glycosylation states.

项目概要 Neurexin 是突触前神经元上重要的细胞粘附分子，介导重要的结合事件形成突触，神经元通讯的最基本单位。神经毒素结构的改变是许多认知和神经系统疾病的基础。我们对神经毒素结构的有限了解阻碍了我们开发靶向疗法来缓解这些疾病的能力。最近的发现发现神经毒素装饰有多种糖胺聚糖结构的糖缀合物。这些发现令人兴奋且迅速对神经毒素结构结合有全面且依赖于聚糖的理解的要求关系。然而，鉴于研究的多样性和异质性，此类研究具有挑战性。糖胺聚糖。使用植根于化学生物学的创新蛋白多糖编辑平台，我们将构建已定义并补充的神经蛋白胞外域，并完善与已知结合伙伴的结合关系（评估阶段，目标 1）。随后，我们将把这些分子应用到活的原代神经元上并展示它们在细胞表面以从头的方式，这样我们就可以使用邻近标记来捕获它们相应的相互作用组（发现阶段，目标 2）。这些复杂的材料将作为重要的工具来定义和评估神经毒素配体，该应用程序的总体结果将是神经毒素目录由其糖基化状态定义的相互作用组。