The Macromolecular Architecture of Extracellular Domain of αNRXN1: Domain Organization, Flexibility, and Insights into Trans-Synaptic Disposition

Neurexins are multidomain synaptic cell-adhesion proteins that associate with multiple partnering proteins. Genetic evidence indicates that neurexins may contribute to autism, schizophrenia, and nicotine dependence. Using analytical ultracentrifugation, single-particle electron microscopy, and solution X-ray scattering, we obtained a three-dimensional structural model of the entire extracellular domain of neurexin-1 alpha. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution, with a maximum dimension of similar to 170 angstrom. The extracellular domain of alpha-neurexin maintains a characteristic Y shape, whereby LNS domains 1-4 form an extended base of the Y and LNS5-6 the shorter arms. Moreover, two major regions of flexibility are present: one between EGF1 and LNS2, corresponding to splice site 1, another between LNS5 and 6. We thus provide the first structural insights into the architecture of the extracellular region of neurexin-1 alpha, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously.