title: The macromolecular architecture of extracellular domain of alphaNRXN1: domain organization, flexibility, and insights into trans-synaptic disposition.
abstract: 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-1alpha. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution, with a maximum dimension of approximately 170 A. 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-1alpha, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously.
authors.affiliation: Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. dcomolet@ucsd.edu
authors.forename: Davide
authors.initials: D
authors.lastname: Comoletti
authors.forename: Meghan T
authors.initials: MT
authors.lastname: Miller
authors.forename: Cy M
authors.initials: CM
authors.lastname: Jeffries
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wilson
authors.forename: Borries
authors.initials: B
authors.lastname: Demeler
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
authors.forename: Jill
authors.initials: J
authors.lastname: Trewhella
authors.forename: Terunaga
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry*; D006801:Humans; D008854:Microscopy, Electron; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D019006:Neural Cell Adhesion Molecules; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013569:Synapses / Q000378:metabolism*; D014461:Ultracentrifugation; D014961:X-Ray Diffraction
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules