Gephyrin
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| Location (UCSC) | Chr 14: 66.51 – 67.18 Mb | Chr 12: 78.27 – 78.73 Mb | |||||||
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Gephyrin is a protein that in humans is encoded by the GPHN gene.[5][6][7][8][9]
This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperekplexia and also lead to molybdenum cofactor deficiency.
Gene
Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known.
Function
Gephyrin is a 93kDa multi-functional
Positive
Gephyrin displaces GABA receptors from the
The gephyrin protein is also required for insertion of molybdenum into molybdopterin.[19]
As aforementioned, gephyrin also catalyzes terminal two steps of Moco biosynthesis. In the penultimate step, N-terminal G domain adenylate the apo form of the molybdopterin to form the intermediate adenylated molybdopterin. In the terminal step, the C-terminal E domain catalyzes the deadenylation and also the metal insertion mechanism.
Clinical significance
Humans with
Yin-yang sequences
At some point in human history, there was a DNA sequence encompassing gephyrin that split and followed two divergent evolutionary paths.[10] These types of splits can occur when two populations become isolated from each other or when a chromosomal region does not experience recombination events. The two sequences that split from the ancestral sequence each acquired more than a hundred mutations that subsequently became common. This happened in a relatively short time on an evolutionary scale, as hundreds of mutations were fixed in distinct ‘yin’ and ‘yang’ sequences prior to human migration to Asia. It has been reported that currently Asians carry nearly equal numbers of yin and yang sequences and global populations representing every major human ancestry possess both yin and yang sequences.[10] The existence of this massive yin-yang pattern suggests that two completely divergent evolutionary paths rapidly progressed during human history, presumably achieving the common goal of enhancing regulation of gephyrin.
Interactions
GPHN has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000171723 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047454 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 1319186.
- ^ PMID 10325225.
- S2CID 6885626.
- ^ a b "Entrez Gene: GPHN gephyrin".
- ^ PMID 24920633.
- ^ PMID 25813846.*Lay summary in: "Big data allows computer engineers to find genetic clues in humans". ScienceDaily. March 27, 2015.
- PMID 24100323.
- PMID 12967995.
- PMID 17293395.
- PMID 22006921.
- ISBN 978-1-4614-4370-4.
- ^ S2CID 24878249.
- S2CID 15911502.
- ^ PMID 22615685.
- S2CID 41013043.
- S2CID 12025675.
Further reading
- Sassoè-Pognetto M, Fritschy JM (2000). "Mini-review: gephyrin, a major postsynaptic protein of GABAergic synapses". Eur. J. Neurosci. 12 (7): 2205–10. S2CID 46305641.
- Reiss J, Johnson JL (2003). "Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH". Hum. Mutat. 21 (6): 569–76. S2CID 41013043.
- Kirsch J, Langosch D, Prior P, Littauer UZ, Schmitt B, Betz H (1991). "The 93-kDa glycine receptor-associated protein binds to tubulin". J. Biol. Chem. 266 (33): 22242–5. PMID 1657993.
- Lorenzo LE, Barbe A, Bras H (March 2004). "Mapping and quantitative analysis of gephyrin cytoplasmic trafficking pathways in motoneurons, using an optimized Transmission Electron Microscopy Color Imaging (TEMCI) procedure". Journal of Neurocytology. 33 (2): 241–9. S2CID 24964320.
- Meyer G, Kirsch J, Betz H, Langosch D (1995). "Identification of a gephyrin binding motif on the glycine receptor beta subunit". Neuron. 15 (3): 563–72. PMID 7546736.
- Mammoto A, Sasaki T, Asakura T, Hotta I, Imamura H, Takahashi K, Matsuura Y, Shirao T, Takai Y (1998). "Interactions of drebrin and gephyrin with profilin". Biochem. Biophys. Res. Commun. 243 (1): 86–9. PMID 9473484.
- Kneussel M, Hermann A, Kirsch J, Betz H (1999). "Hydrophobic interactions mediate binding of the glycine receptor beta-subunit to gephyrin". J. Neurochem. 72 (3): 1323–6. PMID 10037506.
- Kins S, Betz H, Kirsch J (2000). "Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin". Nat. Neurosci. 3 (1): 22–9. S2CID 24878249.
- Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O (2000). "Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro". DNA Res. 7 (1): 65–73. PMID 10718198.
- Butler MH, Hayashi A, Ohkoshi N, Villmann C, Becker CM, Feng G, De Camilli P, Solimena M (2000). "Autoimmunity to gephyrin in Stiff-Man syndrome". Neuron. 26 (2): 307–12. PMID 10839351.
- Kneussel M, Haverkamp S, Fuhrmann JC, Wang H, Wässle H, Olsen RW, Betz H (2000). "The γ-aminobutyric acid type A receptor (GABAAR)-associated protein GABARAP interacts with gephyrin but is not involved in receptor anchoring at the synapse". Proc. Natl. Acad. Sci. U.S.A. 97 (15): 8594–9. PMID 10900017.
- Reiss J, Gross-Hardt S, Christensen E, Schmidt P, Mendel RR, Schwarz G (2001). "A Mutation in the Gene for the Neurotransmitter Receptor–Clustering Protein Gephyrin Causes a Novel Form of Molybdenum Cofactor Deficiency". Am. J. Hum. Genet. 68 (1): 208–13. PMID 11095995.
- David-Watine B (2001). "The human gephyrin (GPHN) gene: structure, chromosome localization and expression in non-neuronal cells". Gene. 271 (2): 239–45. PMID 11418245.
- Schwarz G, Schrader N, Mendel RR, Hecht HJ, Schindelin H (2001). "Crystal structures of human gephyrin and plant Cnx1 G domains: comparative analysis and functional implications". J. Mol. Biol. 312 (2): 405–18. PMID 11554796.
- Grosskreutz Y, Hermann A, Kins S, Fuhrmann JC, Betz H, Kneussel M (2002). "Identification of a gephyrin-binding motif in the GDP/GTP exchange factor collybistin". Biol. Chem. 382 (10): 1455–62. S2CID 2415901.
- Fuhrmann JC, Kins S, Rostaing P, El Far O, Kirsch J, Sheng M, Triller A, Betz H, Kneussel M (2002). "Gephyrin interacts with Dynein light chains 1 and 2, components of motor protein complexes". J. Neurosci. 22 (13): 5393–402. PMID 12097491.
- Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. PMID 12477932.
- Waldvogel HJ, Baer K, Snell RG, During MJ, Faull RL, Rees MI (2003). "Distribution of gephyrin in the human brain: an immunohistochemical analysis". Neuroscience. 116 (1): 145–56. S2CID 32101833.
External links
- GPHN human gene location in the UCSC Genome Browser.
- GPHN human gene details in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: Q9NQX3 (Gephyrin) at the PDBe-KB.
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