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Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain.
J Biol Chem. 2014 Oct 03; 289(40):27585-603.JB

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+Show Affiliations

From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany.From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany.From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany.From the Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, 48149 Münster, Germany.Institute of Medical Physics and Biophysics, Westfälische Wilhelms-University, Robert-Koch Strasse 31, 48149 Münster, Germany, and.Institute of Medical Physics and Biophysics, Westfälische Wilhelms-University, Robert-Koch Strasse 31, 48149 Münster, Germany, and.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25157101

Citation

Reissner, Carsten, et al. "Dystroglycan Binding to Α-neurexin Competes With Neurexophilin-1 and Neuroligin in the Brain." The Journal of Biological Chemistry, vol. 289, no. 40, 2014, pp. 27585-603.
Reissner C, Stahn J, Breuer D, et al. Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain. J Biol Chem. 2014;289(40):27585-603.
Reissner, C., Stahn, J., Breuer, D., Klose, M., Pohlentz, G., Mormann, M., & Missler, M. (2014). Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain. The Journal of Biological Chemistry, 289(40), 27585-603. https://doi.org/10.1074/jbc.M114.595413
Reissner C, et al. Dystroglycan Binding to Α-neurexin Competes With Neurexophilin-1 and Neuroligin in the Brain. J Biol Chem. 2014 Oct 3;289(40):27585-603. PubMed PMID: 25157101.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain. AU - Reissner,Carsten, AU - Stahn,Johanna, AU - Breuer,Dorothee, AU - Klose,Martin, AU - Pohlentz,Gottfried, AU - Mormann,Michael, AU - Missler,Markus, Y1 - 2014/08/25/ PY - 2014/8/27/entrez PY - 2014/8/27/pubmed PY - 2014/12/18/medline KW - Adhesion KW - Autism KW - Disulfide KW - Glycomics KW - Molecular Modeling KW - Site-directed Mutagenesis SP - 27585 EP - 603 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 289 IS - 40 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/25157101/Dystroglycan_binding_to_α_neurexin_competes_with_neurexophilin_1_and_neuroligin_in_the_brain_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=25157101 DB - PRIME DP - Unbound Medicine ER -