Universität zu Köln 

Prof. Dr. Günter Schwarz

Institut für Biochemie, Universität zu Köln
email: gschwarz@uni-koeln.de
phone: +49-(0)221 470 6440
website

Anchoring and clustering of neuroreceptors is vital for proper signal transmission in the central nervous system. The protein gephyrin plays a critical role in organising postsynaptic structures at glycinergic and GABAergic synapses. We determined structures of both, the N- and C-terminal domain of gephyrin, identified the binding site of the glycine receptor and described key motifs for gephyrin clustering. Although a number of gephyrin-interacting proteins have been identified in the past it remained enigmatic how conformational changes in gephyrin affect gephyrin clustering, receptor binding and synpatogenesis. Recently, we and others found that gephyrin is a post-synaptic phosphoprotein as well as membrane-attached via palmitoylation. In this project we therefore aim to identify key phosphorylation sites being crucial for gephyrin clustering, the respective kinases and the underlying structural and functional changes. Furthermore, we will identify the palmitoylation site(s), the respective palmitoyl transferase and the functional impact on receptor targeting and clustering.

Running time: 07/2011 – 06/2015

Recent publications:

Herweg, J., Schwarz, G. (2012). Splice-specific glycine receptor binding, folding, and phosphorylation of the scaffolding protein gephyrin. J. Biol. Chem. 287, 12645-56.

Lambeck, I., Fischer-Schrader, K., Nick, D., Röper, J., Chi, J.C., Hille, R., Schwarz, G. (2012).? The molecular mechanism of 14-3-3-mediated inhibition of plant nitrate reductase. J. Biol. Chem. 287, 4562-4571, (A 5). PubMed

??Ogino, K., Ramsden, S.L., Keib, N., Schwarz, G., Harvey, R.J., Hirata, H. (2011). Duplicated gephyrin genes showing distinct tissue distribution and alternative splicing patterns mediate molybdenum cofactor biosynthesis, glycine receptor clustering, and escape behavior in zebrafish. J. Biol. Chem. 286, 806-17.

Forstera, B., Belaidi, A.A., Juttner, R., Bernert, C., Tsokos, M., Lehmann, T.N., Horn, P., Dehnicke, C., Schwarz, G., and Meier, J.C. (2010). Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy. Brain 133, 3778-94.

Fritschy, J.M., Harvey, R.J., and Schwarz, G. (2008). Gephyrin: where do we stand, where do we go? Trends Neurosci. 31, 257-264.

Smolinsky, B., Eichler, S.A., Buchmeier, S., Meier, J.C., and Schwarz, G. (2008). Splice-specific functions of gephyrin in molybdenum cofactor biosynthesis. J. Biol. Chem. 283, 17370-17379.

Lardi-Studler, B., Smolinsky, B., Petitjean, C.M., Koenig, F., Sidler, C., Meier, J.C., Fritschy, J.M., and Schwarz, G. (2007). Vertebrate-specific sequences in the gephyrin E-domain regulate cytosolic aggregation and postsynaptic clustering. J. Cell Sci. 120, 1371-1382.

Kim, E.Y., Schrader, N., Smolinsky, B., Bedet, C., Vannier, C., Schwarz, G., and Schindelin, H. (2006). Deciphering the structural framework of glycine receptor anchoring by gephyrin. EMBO J. 25, 1385-1395.

Xiang, S., Kim, E.Y., Connelly, J.J., Nassar, N., Kirsch, J., Winking, J., Schwarz, G., and Schindelin, H. (2006). The crystal structure of Cdc42 in complex with collybistin II, a gephyrin-interacting guanine nucleotide exchange factor. J. Mol. Biol. 359, 35-46.

Schrader, N., Kim, E.Y., Winking, J., Paulukat, J., Schindelin, H., and Schwarz, G. (2004). Biochemical characterization of the high affinity binding between the glycine receptor and gephyrin. J. Biol. Chem. 279, 18733-18741.