Mapping glycan-dependent neurexin interactomes

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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.