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169 a.a.
Key reference
DOI no: 10.1074/jbc.M101923200 J Biol Chem 276:25294-25301 (2001) PubMed id: 11325967
X-ray crystal structure of the trimeric N-terminal domain of gephyrin. M.Sola, M.Kneussel, I.S.Heck, H.Betz, W.Weissenhorn. ABSTRACT
Gephyrin is a ubiquitously expressed protein that, in the central nervous system, forms a submembraneous scaffold for anchoring inhibitory neurotransmitter receptors in the postsynaptic membrane. The N- and C-terminal domains of gephyrin are homologous to the Escherichia coli enzymes MogA and MoeA, respectively, both of which are involved in molybdenum cofactor biosynthesis. This enzymatic pathway is highly conserved from bacteria to mammals, as underlined by the ability of gephyrin to rescue molybdenum cofactor deficiencies in different organisms. Here we report the x-ray crystal structure of the N-terminal domain (amino acids 2-188) of rat gephyrin at 1.9-A resolution. Gephyrin-(2-188) forms trimers in solution, and a sequence motif thought to be involved in molybdopterin binding is highly conserved between gephyrin and the E. coli protein. The atomic structure of gephyrin-(2-188) resembles MogA, albeit with two major differences. The path of the C-terminal ends of gephyrin-(2-188) indicates that the central and C-terminal domains, absent in this structure, should follow a similar 3-fold arrangement as the N-terminal region. In addition, a central beta-hairpin loop found in MogA is lacking in gephyrin-(2-188). Despite these differences, both structures show a high degree of surface charge conservation, which is consistent with their common catalytic function.
Selected figure(s)
Figure 2.
Fig. 2. Ribbon diagram of gephyrin-(2-188). a (top view), secondary structure elements are labeled for one monomer. The positions of proposed active sites (MPT) are indicated by black arrows. Cter, C terminus; Nter, N terminus. b (side view), shows the path of the C-terminal-helix 8 connecting to the intervening domain of gephyrin. Positions of possible sequence insertions in differentially spliced gephyrin variants are indicated by yellow arrows (1, cassette 1; 5, cassette 5). C (close-up view), the linker sequence in stereo. Hydrogen bonds are shown as dashed lines. Figs. 2 and 5b were generated using the program MOLMOL (46).
Figure 4.
Fig. 4. Electrostatic potential maps of gephyrin-(2-188) (a and c) and MogA (b and d). Regions where electrostatic potential <30 k[B]T are shown in red and those > +30 k[B]T are shown in blue (k[B], Boltzmann constant; T, absolute temperature). The surface changes between the gephyrin-(2-188) and the E. coli MogA structures caused by the insertion of a loop in MogA and the different paths of the C-terminal ends are indicated by yellow arrows. The surfaces viewed from the top (a and b) and bottom (c and d). White arrows indicate slight differences in the trimer interface as seen from the top.
The above figures are reprinted by permission from the ASBMB: J Biol Chem (2001, 276, 25294-25301) copyright 2001. Figures were selected by an automated process.
Literature references that cite this PDB file's key reference
PubMed id Reference
18719933 T.Dresbach, R.Nawrotzki, T.Kremer, S.Schumacher, D.Quinones, M.Kluska, J.Kuhse, and J.Kirsch (2008).
Molecular architecture of glycinergic synapses.Histochem Cell Biol, 130, 617-633.
17347650 M.M.Zita, I.Marchionni, E.Bottos, M.Righi, G.Del Sal, E.Cherubini, and P.Zacchi (2007).
Post-phosphorylation prolyl isomerisation of gephyrin represents a mechanism to modulate glycine receptors function.EMBO J, 26, 1761-1771.
16449194 C.Maas, N.Tagnaouti, S.Loebrich, B.Behrend, C.Lappe-Siefke, and M.Kneussel (2006).
Neuronal cotransport of glycine receptor and the scaffold protein gephyrin.J Cell Biol, 172, 441-451.
15739236 B.Studler, C.Sidler, and J.M.Fritschy (2005).
Differential regulation of GABA(A) receptor and gephyrin postsynaptic clustering in immature hippocampal neuronal cultures.J Comp Neurol, 484, 344-355.
15159566 G.Bader, M.Gomez-Ortiz, C.Haussmann, A.Bacher, R.Huber, and M.Fischer (2004).
Structure of the molybdenum-cofactor biosynthesis protein MoaB of Escherichia coli.Acta Crystallogr D Biol Crystallogr, 60, 1068-1075.
PDB code: 1r2k
15201864 M.Sola, V.N.Bavro, J.Timmins, T.Franz, S.Ricard-Blum, G.Schoehn, R.W.Ruigrok, I.Paarmann, T.Saiyed, G.A.O'Sullivan, B.Schmitt, H.Betz, and W.Weissenhorn (2004).
Structural basis of dynamic glycine receptor clustering by gephyrin.EMBO J, 23, 2510-2519.
PDB code: 1t3e 12072459 I.S.Heck, J.D.Schrag, J.Sloan, L.J.Millar, G.Kanan, J.R.Kinghorn, and S.E.Unkles (2002).
Mutational analysis of the gephyrin-related molybdenum cofactor biosynthetic gene cnxE from the lower eukaryote Aspergillus nidulans.Genetics, 161, 623-632.
11727829 Y.Grosskreutz, A.Hermann, S.Kins, J.C.Fuhrmann, H.Betz, and M.Kneussel (2001).
Identification of a gephyrin-binding motif in the GDP/GTP exchange factor collybistin.Biol Chem, 382, 1455-1462. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
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