Structural basis of dynamic glycine receptor clustering by gephyrin.

Journal article

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: Sola, M; Bavro, V; Timmins, J; Franz, T; Ricard-Blum, S

• Publication status: Published
• Journal: EMBO journal
• Volume: 23
• Issue: 13
• Pages: 2510-2519
• Publication date: 2004-07-01
• DOI: 10.1038/sj.emboj.7600256
• EISSN: 1460-2075
• ISSN: 0261-4189
• Language: English
• Keywords: Surface Plasmon Resonance; Receptors, Glycine; Models, Chemical; Solutions; Trypsin; Crystallography, X-Ray; Peptide Fragments; Dimerization; Binding Sites; Protein Conformation; Animals; Carrier Proteins; Synapses; Chromatography, Gel; Protein Binding; Hydrogen-Ion Concentration; Protein Subunits; Coenzymes; Membrane Proteins; Sulfates; Mass Spectrometry; Models, Molecular; Metalloproteins; Pteridines; Protein Structure, Tertiary; Hydrolysis; Rats