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J. Biol. Chem., Vol. 282, Issue 8, 5625-5632, February 23, 2007

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Molecular Basis of Gephyrin Clustering at Inhibitory Synapses

ROLE OF G- AND E-DOMAIN INTERACTIONS^*

Taslimarif Saiyed¹, Ingo Paarmann, Bertram Schmitt, Svenja Haeger, Maria Sola^¶2, Günther Schmalzing, Winfried Weissenhorn^¶, and Heinrich Betz³

From the Department of Neurochemistry, Max Planck Institute for Brain Research, D-60528 Frankfurt/Main, Germany, Department of Molecular Pharmacology, RWTH Aachen University, D-52074 Aachen, Germany, and ^¶European Molecular Biology Laboratory, F-38042 Grenoble Cedex 9, France

Gephyrin is a bifunctional modular protein that, in neurons, clusters glycine receptors and -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 -subunit binding region prevented the localization of the clusters at synaptic sites. Together our findings show that domain interactions mediate gephyrin scaffold formation.

Received for publication, November 3, 2006 , and in revised form, December 19, 2006.

^* This work was supported in part by Max-Planck-Gesellschaft, Deutsche Forschungsgemeinschaft (SFB628 and Schm536/4-1) and Fonds der Chemischen Industrie. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Max-Planck predoctoral fellowship.

² Present address: Dept. of Structural Biology, IBMB-CSIC, 08028 Barcelona, Spain.

³ To whom correspondence should be addressed: Dept. of Neurochemistry, Max Planck Institute for Brain Research, Deutschordenstr. 46, D-60528 Frankfurt, Germany. Fax: 49-69-96769-441; E-mail: neurochemie{at}mpih-frankfurt.mpg.de.

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