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Elucidating Dynamic Interactions of Neuroligin4 with Alpha and [Beta]-Neurexin1 via Deuterium Exchange Mass Spectrometry /


Synaptic adhesion molecules such as neuroligins and neurexins play a critical role in nervous system development and aberrations in their structure appear associated with developmental conditions such as the Autism Spectrum Disorders. Yet why two distinct [alpha]- and [beta]- neurexin protein isoforms emerged in the synapse is still not well understood. Neurexins are composed of either [alpha]- forms containing six distinct Laminin-Neurexin-Sex (LNS 1-6) hormone binding globulin domains and three epidermal growth factor like domains (EGF 1-3), and [beta]- forms which are solely composed of the sixth LNS domain. Both serve as presynaptic cell adhesion molecules and bind to postsynaptic neuroligins which are members of the [alpha]-[beta] hydrolase fold family. It is hypothesized that though binding of neuroligin to neurexins is strongest at the sixth LNS domain, or [beta]-neurexin, it may not have to occur there exclusively due to established variance in protein function. Hydrogen/Deuterium Exchange Mass Spectrometry (DXMS) was utilized to elucidate the structural components of neuroligin4 and [alpha]- and [beta]-neurexin1 and probe for changes induced by binding interactions. This revealed in neuroligin a novel point of interaction with [alpha]- neurexin through reductions in deuterium exchange rates absent when bound to [beta]-neurexin1. [Alpha]-neurexin1 exchange profiles also affirmed physical occlusion at LNS 4 and 5 yet neuroligin's binding site remained specific to LNS 6. Furthermore [beta]-neurexin1 displayed binding trends highly similar to [alpha]-neurexin1's LNS 6 and confirmed that both bind neuroligin4 in the same fashion and that potential neuroligin interaction with LNS 4 and 5 exert minimal effects on LNS 6 binding

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