Structural basis of dynamic glycine receptor clustering by gephyrin |
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| Authors: | Sola Maria Bavro Vassiliy N Timmins Joanna Franz Thomas Ricard-Blum Sylvie Schoehn Guy Ruigrok Rob W H Paarmann Ingo Saiyed Taslimarif O'Sullivan Gregory A Schmitt Bertram Betz Heinrich Weissenhorn Winfried |
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| Affiliation: | European Molecular Biology Laboratory, Grenoble, France. |
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| 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. |
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