title: The structure of neurexin 1α reveals features promoting a role as synaptic organizer.
abstract: α-neurexins are essential synaptic adhesion molecules implicated in autism spectrum disorder and schizophrenia. The α-neurexin extracellular domain consists of six LNS domains interspersed by three EGF-like repeats and interacts with many different proteins in the synaptic cleft. To understand how α-neurexins might function as synaptic organizers, we solved the structure of the neurexin 1α extracellular domain (n1α) to 2.65 Å. The L-shaped molecule can be divided into a flexible repeat I (LNS1-EGF-A-LNS2), a rigid horseshoe-shaped repeat II (LNS3-EGF-B-LNS4) with structural similarity to so-called reelin repeats, and an extended repeat III (LNS5-EGF-B-LNS6) with controlled flexibility. A 2.95 Å structure of n1α carrying splice insert SS#3 in LNS4 reveals that SS#3 protrudes as a loop and does not alter the rigid arrangement of repeat II. The global architecture imposed by conserved structural features enables α-neurexins to recruit and organize proteins in distinct and variable ways, influenced by splicing, thereby promoting synaptic function.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.forename: Vandavasi
authors.initials: V
authors.lastname: Venugopal
authors.forename: Beverly
authors.initials: B
authors.lastname: Murray
authors.forename: Gabby
authors.initials: G
authors.lastname: Rudenko
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D002417:Cattle; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry*; D008958:Models, Molecular; D009479:Neuropeptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry*; D013499:Surface Properties; D013569:Synapses / Q000737:chemistry*
chemical_list: D006023:Glycoproteins; D009479:Neuropeptides; D011994:Recombinant Proteins; C112162:neurexophilin; D002118:Calcium