title: Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin.
abstract: γ-Aminobutyric acid type A and glycine receptors (GABA(A)Rs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABA(A)Rs are important drug targets regulated by direct interactions with the scaffolding protein gephyrin. Here we deduce the molecular basis of this interaction by chemical, biophysical and structural studies of the gephyrin-GABA(A)R α3 complex, revealing that the N-terminal region of the α3 peptide occupies the same binding site as the GlyR β subunit, whereas the C-terminal moiety, which is conserved among all synaptic GABA(A)R α subunits, engages in unique interactions. Thermodynamic dissections of the gephyrin-receptor interactions identify two residues as primary determinants for gephyrin's subunit preference. This first structural evidence for the gephyrin-mediated synaptic accumulation of GABA(A)Rs offers a framework for future investigations into the regulation of inhibitory synaptic strength and for the development of mechanistically and therapeutically relevant compounds targeting the gephyrin-GABA(A)R interaction.
authors.affiliation: 1] Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Straße 2, Building D15, D-97080 Würzburg, Germany [2] Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Maric
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Straße 2, Building D15, D-97080 Würzburg, Germany.
authors.forename: Vikram Babu
authors.initials: VB
authors.lastname: Kasaragod
authors.affiliation: Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Torben Johann
authors.initials: TJ
authors.lastname: Hausrat
authors.affiliation: Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.affiliation: Department of General Anesthesia and Intensive Care, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Tretter
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Straße 2, Building D15, D-97080 Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Schindelin
mesh_terms: D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018009:Receptors, Glycine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C546257:GABRA3 protein, human; C114561:GLRB protein, human; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; C073441:gephyrin; D005680:gamma-Aminobutyric Acid