Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin
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Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin. / Maric, Hans Michael; Kasaragod, Vikram Babu; Hausrat, Torben Johann; Kneussel, Matthias; Tretter, Verena; Strømgaard, Kristian; Schindelin, Hermann.
in: NAT COMMUN, Jahrgang 5, 01.01.2014, S. 5767.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin
AU - Maric, Hans Michael
AU - Kasaragod, Vikram Babu
AU - Hausrat, Torben Johann
AU - Kneussel, Matthias
AU - Tretter, Verena
AU - Strømgaard, Kristian
AU - Schindelin, Hermann
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms6767
DO - 10.1038/ncomms6767
M3 - SCORING: Journal article
C2 - 25531214
VL - 5
SP - 5767
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
ER -