Mapping glycan-dependent neurexin interactomes

项目总结 Neuresin是突触前神经元上的一种重要的细胞黏附分子，介导重要的结合事件 形成突触，这是神经元交流的最基本单位。神经脲素结构的改变 这是许多认知和神经疾病的基础。我们对Neuresin结构的有限理解阻碍了我们的 有能力开发有针对性的治疗方法来缓解这些疾病。最近的发现发现，纽瑞新是一种 一种装饰有不同糖胺多聚糖结构的糖偶联物。这些发现是令人兴奋和迅速的 对Neuresin结构结合的全面和依赖于糖的理解的要求 两性关系。然而，考虑到生物多样性和异质性，这类研究具有挑战性。 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 构建已定义和丰富的Neuresin胞外结构域，并改进与已知结合伙伴的结合关系 (评价阶段，目标1)。随后，我们将把这些分子应用于活的初级神经元并展示它们 以一种从头开始的方式在细胞表面上，以便我们可以使用邻近标记来捕捉它们对应的 互动(发现阶段，目标2)。这些复杂的材料将作为重要工具来定义和 评估neuresin配体，这一应用的总体结果将是neuresin的目录 由糖基化状态定义的相互作用。

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.