Browsing by Author "Comoletti, D"

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    Macromolecular architecture of extracellular domain of αNRXN1: domain organization, flexibility, and insights into trans-synaptic disposition.
    (Elsevier (Cell Press), 2010-08-11) Comoletti, D; Miller, MT; Jeffries, CM; Wilson, J; Demeler, B; Taylor, P; Trewhella, J; Nakagawa, T
    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-1α. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution, with a maximum dimension of ~ 170 Å. The extracellular domain of α-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-1α, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously. © 2010, Cell Press
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    Synaptic arrangement of the neuroligin/β-neurexin complex revealed by x-ray and neutron scattering
    (Elsevier (Cell Press), 2007-06) Comoletti, D; Grishaev, A; Whitten, AE; Tsignelny, I; Taylor, P; Trewhella, J
    Neuroligins are postsynaptic cell-adhesion proteins that associate with their presynaptic partners, the neurexins. Using small-angle X-ray scattering, we determined the shapes of the extracellular region of several neuroligin isoforms in solution. We conclude that the neuroligins dimerize via the characteristic four-helix bundle observed in cholinesterases, and that the connecting sequence between the globular lobes of the dimer and the cell membrane is elongated, projecting away from the dimer interface. X-ray scattering and neutron contrast variation data show that two neurexin monomers, separated by 107 A, bind at symmetric locations on opposite sides of the long axis of the neuroligin dimer. Using these data, we developed structural models that delineate the spatial arrangements of different neuroligin domains and their partnering molecules. As mutations of neurexin and neuroligin genes appear to be linked to autism, these models provide a structural framework for understanding altered recognition by these proteins in neurodevelopmental disorders. © 2007, Cell Press