title: The crystal structure of the α-neurexin-1 extracellular region reveals a hinge point for mediating synaptic adhesion and function.
abstract: α- and β-neurexins (NRXNs) are transmembrane cell adhesion proteins that localize to presynaptic membranes in neurons and interact with the postsynaptic neuroligins (NLGNs). Their gene mutations are associated with the autism spectrum disorders. The extracellular region of α-NRXNs, containing nine independently folded domains, has structural complexity and unique functional characteristics, distinguishing it from the smaller β-NRXNs. We have solved the X-ray crystal structure of seven contiguous domains of the α-NRXN-1 extracellular region at 3.0 Å resolution. The structure reveals an arrangement where the N-terminal five domains adopt a more rigid linear conformation and the two C-terminal domains form a separate arm connected by a flexible hinge. In an extended conformation the molecule is suitably configured to accommodate a bound NLGN molecule, as supported by structural comparison and surface plasmon resonance. These studies provide the structural basis for a multifunctional synaptic adhesion complex mediated by α-NRXN-1.
authors.affiliation: Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. m4miller@ucsd.edu
authors.forename: Meghan T
authors.initials: MT
authors.lastname: Miller
authors.forename: Mauro
authors.initials: M
authors.lastname: Mileni
authors.forename: Davide
authors.initials: D
authors.lastname: Comoletti
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Michal
authors.initials: M
authors.lastname: Harel
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D002417:Cattle; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000502:physiology; D018360:Crystallography, X-Ray; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry*; D020349:Surface Plasmon Resonance; D013569:Synapses / Q000737:chemistry*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D002118:Calcium