Gephyrin

Gephyrin is a protein that in humans is encoded by the GPHN gene.[5][6][7][8][9]

GPHN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGPHN, GEPH, GPH, GPHRYN, HKPX1, MOCODC, gephyrin
External IDsOMIM: 603930 MGI: 109602 HomoloGene: 10820 GeneCards: GPHN
Gene location (Human)
Chr.Chromosome 14 (human)[1]
Band14q23.3-q24.1Start66,507,407 bp[1]
End67,181,803 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

10243

268566

Ensembl

ENSG00000171723

ENSMUSG00000047454

UniProt

Q9NQX3

Q8BUV3

RefSeq (mRNA)

NM_145965
NM_172952

RefSeq (protein)

NP_666077
NP_766540

Location (UCSC)Chr 14: 66.51 – 67.18 MbChr 12: 78.23 – 78.68 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[8] The production of alternatively spliced variants is affected by noncoding regions within the gene. A ‘yin-yang’ noncoding sequence pair encompassing gephyrin has been identified.[10] These sequences are opposites of each other - consisting of hundreds of divergent nucleotide states. Both of these patterns are uniquely human and evolved rapidly after splitting from their ancestral DNA pattern. The gephyrin yin and yang sequences are prevalent today in populations representing every major human ancestry.

Function

Gephyrin is a 93kDa multi-functional protein that is a component of the postsynaptic protein network of inhibitory synapses. It consists of 3 domains: N terminal G domain, C terminal E domain, and a large unstructured linker domain which connects the two. Although there are structures available for trimeric G and dimeric E domains, there is no structure available for the full length protein, which may be due to the large unstructured region which makes the protein hard to crystallize. But a recent study of the full length gephyrin by small-angle X-ray scattering shows that it predominantly forms trimers, and that because of its long linker region, it can exist in either a compact state or either of two extended states.[11]

Positive antibody staining for gephyrin at a synapse is most of the time consistent with the presence of glycine and/or GABAA receptors. Nevertheless, some exceptions can occur like in neurons of Dorsal Root Ganglions where gephyrin is absent despite the presence of GABAA receptors.[9] Gephyrin is considered a major scaffolding protein at inhibitory synapses, analogous in its function to that of PSD-95 at glutamatergic synapses.[12][13] Gephyrin was identified by its interaction with the glycine receptor, the main receptor protein of inhibitory synapses in the spinal cord and brainstem. In addition to its interaction with the glycine receptor, recent publications have shown that gephyrin also interacts with the intracellular loop between the transmembrane helices TM3 and TM4 of alpha and beta subunits of the GABAA receptor.[14]

Gephyrin displaces GABA receptors from the GABARAP/P130 complex, then brings the receptors to the synapse.[15] Once at the synapse, the protein binds to collybistin[16] and neuroligin 2.[17] In cells, gephyrin appears to form oligomers of at least three subunits. Several splice variants have been described that prevent this oligomerization without influencing the affinity for receptors. They nevertheless affect the composition of inhibitory synapses and can even play a role in diseases like epilepsy.[18]

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 temporal lobe epilepsy have been found to have abnormally low levels of gephyrin in their temporal lobes.[20] In animal models, a total lack of gephyrin results in stiff muscles and death immediately after birth. Stiff muscles are also a symptom of startle disease, that can be caused by a mutation in the gephyrin gene. And if a person produces auto-antibodies against gephyrin, this can even result in stiff person syndrome.[18]

Yin-yang sequences
Yin-yang DNA sequences encompassing human gephyrin gene. Yin-yang haplotypes arise when a stretch of DNA evolves to present two divergent forms. This image shows the states for ~1000 markers in the genomic region centered on gephyrin for 934 individuals in eight global populations. Humans carry pairs of chromosomes, so each individual possesses two copies of the gephyrin gene. Dark blue and red horizontal lines in the yin-yang region represent individuals carrying two yin and two yang haplotypes, respectively, and light blue represents individuals carrying both a yin and a yang haplotype.

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 interact with Mammalian target of rapamycin[6] and ARHGEF9.[16]

References
  1. GRCh38: Ensembl release 89: ENSG00000171723 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000047454 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Prior P, Schmitt B, Grenningloh G, Pribilla I, Multhaup G, Beyreuther K, Maulet Y, Werner P, Langosch D, Kirsch J (Jul 1992). "Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein". Neuron. 8 (6): 1161–70. doi:10.1016/0896-6273(92)90136-2. PMID 1319186.
  6. Sabatini DM, Barrow RK, Blackshaw S, Burnett PE, Lai MM, Field ME, Bahr BA, Kirsch J, Betz H, Snyder SH (Jun 1999). "Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling". Science. 284 (5417): 1161–4. doi:10.1126/science.284.5417.1161. PMID 10325225.
  7. Fritschy JM, Harvey RJ, Schwarz G (May 2008). "Gephyrin: where do we stand, where do we go?". Trends Neurosci. 31 (5): 257–64. doi:10.1016/j.tins.2008.02.006. PMID 18403029.
  8. "Entrez Gene: GPHN gephyrin".
  9. Lorenzo LE, Godin AG, Wang F, St-Louis M, Carbonetto S, Wiseman PW, Ribeiro-da-Silva A, De Koninck Y (June 2014). "Gephyrin Clusters Are Absent from Small Diameter Primary Afferent Terminals Despite the Presence of GABAA Receptors". J. Neurosci. 34 (24): 8300–17. doi:10.1523/JNEUROSCI.0159-14.2014. PMC 6608243. PMID 24920633.
  10. Climer S, Templeton AR, Zhang W (2015). "Human gephyrin is encompassed within giant functional noncoding yin-yang sequences". Nature Communications. 6: 6534. doi:10.1038/ncomms7534. PMC 4380243. PMID 25813846. Lay summary – ScienceDaily.
  11. Sander B, Tria G, Shkumatov AV, Kim EY, Grossmann JG, Tessmer I, Svergun DI, Schindelin H (Oct 2013). "Structural characterization of gephyrin by AFM and SAXS reveals a mixture of compact and extended states". Acta Crystallographica Section D. 69 (Pt 10): 2050–60. doi:10.1107/S0907444913018714. PMID 24100323.
  12. Giesemann T, Schwarz G, Nawrotzki R, Berhörster K, Rothkegel M, Schlüter K, Schrader N, Schindelin H, Mendel RR, Kirsch J, Jockusch BM (September 2003). "Complex formation between the postsynaptic scaffolding protein gephyrin, profilin, and Mena: a possible link to the microfilament system". J. Neurosci. 23 (23): 8330–9. doi:10.1523/JNEUROSCI.23-23-08330.2003. PMC 6740687. PMID 12967995.
  13. Ehrensperger MV, Hanus C, Vannier C, Triller A, Dahan M (May 2007). "Multiple association states between glycine receptors and gephyrin identified by SPT analysis". Biophys. J. 92 (10): 3706–18. doi:10.1529/biophysj.106.095596. PMC 1853151. PMID 17293395.
  14. Maric HM, Mukherjee J, Tretter V, Moss SJ, Schindelin H (December 2011). "Gephyrin-mediated γ-aminobutyric acid type A and glycine receptor clustering relies on a common binding site". J. Biol. Chem. 286 (49): 42105–14. doi:10.1074/jbc.M111.303412. PMC 3234978. PMID 22006921.
  15. Thiriet, Marc (2013). Intracellular Signaling Mediators in the Circulatory and Ventilatory Systems. New York, NY: Springer New York. p. 605. ISBN 978-1-4614-4370-4.
  16. Kins S, Betz H, Kirsch J (January 2000). "Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin". Nat. Neurosci. 3 (1): 22–9. doi:10.1038/71096. PMID 10607391.
  17. Poulopoulos A, Aramuni G, Meyer G, Soykan T, Hoon M, Papadopoulos T, Zhang M, Paarmann I, Fuchs C, Harvey K, Jedlicka P, Schwarzacher SW, Betz H, Harvey RJ, Brose N, Zhang W, Varoqueaux F (September 2009). "Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin". Neuron. 63 (5): 628–42. doi:10.1016/j.neuron.2009.08.023. PMID 19755106.
  18. Tretter V, Mukherjee J, Maric HM, Schindelin H, Sieghart W, Moss SJ (2012). "Gephyrin, the enigmatic organizer at GABAergic synapses". Front Cell Neurosci. 6: 23. doi:10.3389/fncel.2012.00023. PMC 3351755. PMID 22615685.
  19. Reiss J, Johnson JL (June 2003). "Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH". Hum. Mutat. 21 (6): 569–76. doi:10.1002/humu.10223. PMID 12754701.
  20. Fang M, Shen L, Yin H, Pan YM, Wang L, Chen D, Xi ZQ, Xiao Z, Wang XF, Zhou SN (October 2011). "Downregulation of gephyrin in temporal lobe epilepsy neurons in humans and a rat model". Synapse. 65 (10): 1006–14. doi:10.1002/syn.20928. PMID 21404332.

Further reading
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