Molecular Basis of Gephyrin Clustering at Inhibitory Synapses

• Published in: The Journal of biological chemistry Vol. 282; no. 8; pp. 5625 - 5632
• Main Authors: Saiyed, Taslimarif, Paarmann, Ingo, Schmitt, Bertram, Haeger, Svenja, Sola, Maria, Schmalzing, Guönther, Weissenhorn, Winfried, Betz, Heinrich
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 23.02.2007; American Society for Biochemistry and Molecular Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M610290200

Gephyrin is a bifunctional modular protein that, in neurons, clusters glycine receptors and γ-aminobutyric acid, type A receptors in the postsynaptic membrane of inhibitory synapses. By x-ray crystallography and cross-linking, the N-terminal G-domain of gephyrin has been shown to form trimers and the C-terminal E-domain dimers, respectively. Gephyrin therefore has been proposed to form a hexagonal submembranous lattice onto which inhibitory receptors are anchored. Here, crystal structure-based substitutions at oligomerization interfaces revealed that both G-domain trimerization and E-domain dimerization are essential for the formation of higher order gephyrin oligomers and postsynaptic gephyrin clusters. Insertion of the alternatively spliced C5′ cassette into the G-domain inhibited clustering by interfering with trimerization, and mutation of the glycine receptor β-subunit binding region prevented the localization of the clusters at synaptic sites. Together our findings show that domain interactions mediate gephyrin scaffold formation.