Gephyrin (GPHN)
The protein contains 736 amino acids for an estimated molecular weight of 79748 Da.
Microtubule-associated protein involved in membrane protein-cytoskeleton interactions. It is thought to anchor the inhibitory glycine receptor (GLYR) to subsynaptic microtubules (By similarity). Acts as a major instructive molecule at inhibitory synapses, where it also clusters GABA type A receptors (PubMed:25025157, PubMed:26613940).', 'Has also a catalytic activity and catalyzes two steps in the biosynthesis of the molybdenum cofactor. In the first step, molybdopterin is adenylated. Subsequently, molybdate is inserted into adenylated molybdopterin and AMP is released. (updated: Oct. 7, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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Biological Process
Establishment of synaptic specificity at neuromuscular junction
Gamma-aminobutyric acid receptor clustering
Glycine receptor clustering
Mo-molybdopterin cofactor biosynthetic process
Molybdenum incorporation into molybdenum-molybdopterin complex
Molybdopterin cofactor biosynthetic process
Postsynaptic neurotransmitter receptor diffusion trapping
Response to metal ion
Small molecule metabolic process
Vitamin metabolic process
Water-soluble vitamin metabolic process
The reference OMIM entry for this protein is 603930
Gephyrin; gphn
Gph; geph
Kiaa1385 mll/gphn fusion gene, included
DESCRIPTION
The GPHN gene encodes gephyrin, an organizational protein that clusters and localizes the inhibitory glycine and GABA receptors to the microtubular matrix of the neuronal postsynaptic membrane (summary by Rees et al., 2003). To integrate signals from the many synaptic connections on its cell body and dendrites rapidly and specifically, a neuron anchors high concentrations of receptors at postsynaptic sites, matching the correct receptor with the neurotransmitter released from the presynaptic terminal. Receptor-associated proteins are thought to be involved in forming these postsynaptic specializations, possibly by linking the receptor to the postsynaptic cytoskeleton (Kirsch et al., 1993). Gephyrin is essential for both the postsynaptic localization of inhibitory neurotransmitter receptors in the central nervous system and the biosynthesis of the molybdenum cofactor (MoCo) in different peripheral organs (Stallmeyer et al., 1999).CLONING
Prior et al. (1992) cloned the rat gene encoding a 93-kD protein that is associated with the mammalian inhibitory glycine receptor (see 138492). They designated this protein 'gephyrin,' from the Greek word meaning 'bridge,' because it binds with high affinity to polymerized tubulin, suggesting that it may serve as a receptor-microtubule linker. Ramming et al. (2000) described gephyrin splice variants that were differentially expressed in nonneural tissues and different regions of the adult mouse brain. They found that the mouse gephyrin gene shows a highly mosaic organization, with 8 of its 29 exons corresponding to an alternatively spliced region identified by cDNA sequencing. The N- and C-terminal domains of gephyrin, encoded by exons 3-7 and 16-29, respectively, displayed sequence similarities to bacterial, invertebrate, and plant proteins involved in Moco biosynthesis, whereas the central exons 8, 13, and 14 encode motifs that may mediate oligomerization and tubulin binding. The data were consistent with the evolution of gephyrin from a Moco biosynthetic protein by insertion of protein interaction sequences. By searching databases for sequences homologous to rat Geph, Reiss et al. (2001) identified a brain tissue cDNA containing the complete coding sequence of human GPHN. Rees et al. (2003) isolated gephyrin cDNAs and by RT-PCR analysis of human tissues demonstrated the presence of 5 alternatively spliced GPHN exons concentrated in the central linker region of the gene. This region generated 11 distinct GPHN transcript isoforms, with 10 being specific to neuronal tissue.GENE STRUCTURE
Reiss et al. (2001) determined that the GPHN gene contains 22 exons spanning approximately 375 kb.MAPPING
By genomic sequence analysis, Reiss et al. (2001) mapped the GPHN gene to chromosome 14.GENE FUNCTION
Kirsch et al. (1993) demonstrated that gephyrin is essential for localizing the inhibitory glycine receptor to presumptive postsynaptic plasma membrane specializations. Essrich et al. (1998) found that gephyrin is also required for clustering and postsynaptic localization of GABA(A) receptors. Sabatini et al. (1999) determined that gephyrin interacts with RAFT1 (FRAP; 601231) in mammalian cells. RAFT1 is an ATM (607585)-related protein that appears to participate in mitogen-stimulated signaling pathways that control mRNA translation. RAFT1 mutants that could not associate with gephyrin failed to signal to downstream molecules. Sabatini et al. (19 ... More on the omim web site
Oct. 20, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
May 12, 2019: Protein entry updated
Automatic update: model status changed
Nov. 17, 2018: Protein entry updated
Automatic update: model status changed
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
Oct. 27, 2017: Protein entry updated
Automatic update: model status changed
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603930 was added.
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed