title: Structural basis of dynamic glycine receptor clustering by gephyrin.
abstract: Gephyrin is a bi-functional modular protein involved in molybdenum cofactor biosynthesis and in postsynaptic clustering of inhibitory glycine receptors (GlyRs). Here, we show that full-length gephyrin is a trimer and that its proteolysis in vitro causes the spontaneous dimerization of its C-terminal region (gephyrin-E), which binds a GlyR beta-subunit-derived peptide with high and low affinity. The crystal structure of the tetra-domain gephyrin-E in complex with the beta-peptide bound to domain IV indicates how membrane-embedded GlyRs may interact with subsynaptic gephyrin. In vitro, trimeric full-length gephyrin forms a network upon lowering the pH, and this process can be reversed to produce stable full-length dimeric gephyrin. Our data suggest a mechanism by which induced conformational transitions of trimeric gephyrin may generate a reversible postsynaptic scaffold for GlyR recruitment, which allows for dynamic receptor movement in and out of postsynaptic GlyR clusters, and thus for synaptic plasticity.
authors.affiliation: European Molecular Biology Laboratory, Grenoble, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Sola
authors.forename: Vassiliy N
authors.initials: VN
authors.lastname: Bavro
authors.forename: Joanna
authors.initials: J
authors.lastname: Timmins
authors.forename: Thomas
authors.initials: T
authors.lastname: Franz
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ricard-Blum
authors.forename: Guy
authors.initials: G
authors.lastname: Schoehn
authors.forename: Rob W H
authors.initials: RW
authors.lastname: Ruigrok
authors.forename: Ingo
authors.initials: I
authors.lastname: Paarmann
authors.forename: Taslimarif
authors.initials: T
authors.lastname: Saiyed
authors.forename: Gregory A
authors.initials: GA
authors.lastname: O'Sullivan
authors.forename: Bertram
authors.initials: B
authors.lastname: Schmitt
authors.forename: Heinrich
authors.initials: H
authors.lastname: Betz
authors.forename: Winfried
authors.initials: W
authors.lastname: Weissenhorn
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure; D002850:Chromatography, Gel; D003067:Coenzymes / Q000378:metabolism; D018360:Crystallography, X-Ray; D019281:Dimerization; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000737:chemistry / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure; D008667:Metalloproteins / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D000090006:Molybdenum Cofactors; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D011621:Pteridines / Q000378:metabolism; D051381:Rats; D018009:Receptors, Glycine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012996:Solutions; D013431:Sulfates / Q000737:chemistry; D020349:Surface Plasmon Resonance; D013569:Synapses / Q000378:metabolism; D014357:Trypsin / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D003067:Coenzymes; D008565:Membrane Proteins; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D010446:Peptide Fragments; D021122:Protein Subunits; D011621:Pteridines; D018009:Receptors, Glycine; D012996:Solutions; D013431:Sulfates; D014357:Trypsin; C073441:gephyrin; C022261:molybdopterin