title: Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain.
abstract: α-Neurexins (α-Nrxn) are mostly presynaptic cell surface molecules essential for neurotransmission that are linked to neuro-developmental disorders as autism or schizophrenia. Several interaction partners of α-Nrxn are identified that depend on alternative splicing, including neuroligins (Nlgn) and dystroglycan (αDAG). The trans-synaptic complex with Nlgn1 was extensively characterized and shown to partially mediate α-Nrxn function. However, the interactions of α-Nrxn with αDAG, neurexophilins (Nxph1) and Nlgn2, ligands that occur specifically at inhibitory synapses, are incompletely understood. Using site-directed mutagenesis, we demonstrate the exact binding epitopes of αDAG and Nxph1 on Nrxn1α and show that their binding is mutually exclusive. Identification of an unusual cysteine bridge pattern and complex type glycans in Nxph1 ensure binding to the second laminin/neurexin/sex hormone binding (LNS2) domain of Nrxn1α, but this association does not interfere with Nlgn binding at LNS6. αDAG, in contrast, interacts with both LNS2 and LNS6 domains without inserts in splice sites SS#2 or SS#4 mostly via LARGE (like-acetylglucosaminyltransferase)-dependent glycans attached to the mucin region. Unexpectedly, binding of αDAG at LNS2 prevents interaction of Nlgn at LNS6 with or without splice insert in SS#4, presumably by sterically hindering each other in the u-form conformation of α-Nrxn. Thus, expression of αDAG and Nxph1 together with alternative splicing in Nrxn1α may prevent or facilitate formation of distinct trans-synaptic Nrxn·Nlgn complexes, revealing an unanticipated way to contribute to the identity of synaptic subpopulations.
authors.affiliation: From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Reissner
authors.affiliation: From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Stahn
authors.affiliation: From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Breuer
authors.affiliation: From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Klose
authors.affiliation: Institute of Medical Physics and Biophysics, Westfälische Wilhelms-University, Robert-Koch Strasse 31, 48149 Münster, Germany, and.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Pohlentz
authors.affiliation: Institute of Medical Physics and Biophysics, Westfälische Wilhelms-University, Robert-Koch Strasse 31, 48149 Münster, Germany, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Mormann
authors.affiliation: From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany, Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster, Germany markus.missler@uni-muenster.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Missler
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000378:metabolism*; D049030:Dystroglycans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D013569:Synapses / Q000235:genetics / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D008024:Ligands; D009479:Neuropeptides; C112162:neurexophilin; D049030:Dystroglycans
keywords: Adhesion; Autism; Disulfide; Glycomics; Molecular Modeling; Site-directed Mutagenesis