title: Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins.
abstract: Neuroligins 1-4 are postsynaptic transmembrane proteins capable of initiating presynaptic maturation via interactions with beta-neurexin. Both neuroligins and beta-neurexins have alternatively spliced inserts in their extracellular domains. Using analytical ultracentrifugation, we determined that the extracellular domains of the neuroligins sediment as dimers, whereas the extracellular domains of the beta-neurexins appear monomeric. Sedimentation velocity experiments of titrated stoichiometry ratios of beta-neurexin and neuroligin suggested a 2:2 complex formation. The recognition properties of individual neuroligins toward beta-neurexin-1 (NX1beta), along with the influence of their splice inserts, were explored by surface plasmon resonance and affinity chromatography. Different neuroligins display a range of NX1beta affinities spanning more than 2 orders of magnitude. Whereas splice insert 4 in beta-neurexin appears to act only as a modulator of the neuroligin/beta-neurexin association, splice insert B in neuroligin-1 (NL1) is the key element regulating the NL1/NX1beta binding. Our data indicate that gene selection, mRNA splicing, and post-translational modifications combine to give rise to a controlled neuroligin recognition code with a rank ordering of affinities for particular neurexins that is conserved for the neuroligins across mammalian species.
authors.affiliation: Department of Pharmacology, University of California-San Diego, La Jolla, California 92093-0636, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Comoletti
authors.forename: Robyn E
authors.initials: RE
authors.lastname: Flynn
authors.forename: Antony A
authors.initials: AA
authors.lastname: Boucard
authors.forename: Borries
authors.initials: B
authors.lastname: Demeler
authors.forename: Virgil
authors.initials: V
authors.lastname: Schirf
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Lori L
authors.initials: LL
authors.lastname: Jennings
authors.forename: Helen R
authors.initials: HR
authors.lastname: Newlin
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002846:Chromatography, Affinity; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation; D014644:Genetic Variation; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020349:Surface Plasmon Resonance
chemical_list: D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C086959:neurexin Ibeta