Biology:Glutamate-rich protein 3

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Glutamate-rich protein 3, also known as Uncharacterized Protein C1orf173, is a protein encoded by the ERICH3 gene.[1] ERICH3 was named “chromosome 1 open reading frame 173 (C1orf173)” based on its map location in the human genome. It was subsequently renamed “E-rich 3” as a result of the high content of glutamate (E) in its encoded amino acid sequence.[2] Single-nucleotide polymorphisms (SNPs) in the ERICH3 gene has been identified as one of the "top" signals in a genome-wide association study (GWAS) for plasma serotonin concentrations which were themselves associated with selective serotonin reuptake inhibitor (SSRI) response in major depressive disorder (MDD) patients.[3] The same ERICH3 SNP was later demonstrated that was significantly associated with SSRI treatment outcomes in three independent MDD trials,[2][3] including STAR*D,[4] ISPC[5] and PReDICT.[6] ERICH3 is most highly expressed in a variety of regions of the human brain, including the nucleus accumbens (basal ganglia) and frontal cortex based on the GTEx RNA-seq data. The single-cell RNA-seq data for human brain samples revealed that ERICH3 is predominantly expressed in neurons rather than other CNS cell types.[2] ERICH3 was found interacts with proteins function in vesicle biogenesis and may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.[2] ERICH3 protein was also found abundant in blood platelets[7] and cilia[8] based on the proteomic studies. Its function in platelet was thought related to plasma serotonin storage[2] because more than 99% of blood serotonin was stored in platelet[9] and ERICH3 SNPs has been associated with plasma serotonin concentration in MDD patients.[3] ERICH3 in primary cilia might regulates cilium formation and the localizations of ciliary transport.[10]

Gene

The ERICH3 gene in humans is 105,628 bases and is encoded on the minus strand at position 31.1 on the short arm of chromosome 1 from base pair 75,033,795 bp to 75,139,422 bp from pter.[11] ERICH3 RNA was predominantly expressed in human brain and testis based on the GTEx RNA-seq data. The Ensembl human genome assembly annotated five ERICH3 RNA transcripts. The reference transcript consisted of fifteen exons, with exon 14 encoding half of the open reading frame. The reference ERICH3 transcript was expressed in brain, predominantly in neurons but not in testis.[2] A "shorter" ERICH3 transcript consisted of seven exons, of which its first exon mapping to intron 6 of the reference ERICH3 transcript, was predominantly expressed in testis. In addition to ERICH3 vesicular function in antidepressant treatment response and cilium formation, expression of this gene has been linked to several forms of cancer, such as breast cancer and skin sarcomas.[12][13] C1orf173 is expressed in the brain, eye, lung, mammary gland, muscle, pituitary gland, testis, trachea, and uterus.[14]

Protein

The C1orf173 protein in humans is 1,530 amino acids (aa) in length and [15] contains two domains of unknown function, DUF4590 and DUF4543. Both DUF regions are currently uncharacterized though they are found in eukaryotes including humans.[16][17] There are currently three known isoforms of the C1orf173 protein in humans, Q5RHP9-1 (canonical), Q5RHP9-2 and Q5RHP9-3. Other animals tend to have a multitude of variant forms of this gene.[11] The canonical ERICH3 protein, which was encoded from its reference RNA transcript, has been demonstrated is the predominant ERICH3 isoform in neurons by Western blot assays.[2]

verbal caption
A diagram showing the three possible isoforms for the c1orf173 protein.

C1orf173 is predicted to be a nuclear protein based on PSORT II analysis and the suggested protein interactions found between c1orf173 and other proteins such as TAF5L. Analyzing the protein for isoelectric point using the Compute pI/Mw tool in Expasy, it was found that C1orf173 is slightly acidic ranging from a pH of 4.6-5 for most orthologs.[18] Further analysis using the NetPhos tool on Expasy found that there are a large number of phosphorylated serines, an intermediate number of phosphorylated threonines and a few phosphoylated tyrosines.[19]

However, the experimental data clearly showed that ERICH3 proteins, including all three known isoforms, are localized in cytoplasma but not in nucleus.[2] The “canonical” ERICH3 protein was predicted to have a molecular weight (MW) of 168.5 kD, but a band at ~250 kD was observed by Western blot.[2] This striking difference (>80kD) between predicted and observed MWs was unlikely to result from post-translational modification such as glycosylation or phosphorylation but from the high content of glutamate (E) in its amino acid sequence.[2] Previous studies have reported that proteins with a high content of glutamate (E) and/or aspartate (D), amino acids with acidic side chains, can display higher apparent MW values during Western blot analysis than would be predicted.[20]

verbal caption
A diagram showing the two DUF domains and phosphorylation sites (in red) on the domains. Phosphorylated O-Glcnac sites also appear in grey.

Protein Structure

The C1orf173 protein has a secondary structure that is primarily alpha helices and random coils based on bioinformatical analysis.[21][22][23] In humans the tertiary structure of C1orf173 has two components that resemble ubiquitin-like 2 activating enzyme e1b and alginase.[24][25]

Protein Interactions

The C1orf173 protein has been predicted or experimentally observed to interact with the following proteins:


See also

  • C1orf146

References

  1. ↑ Glutamate-Rich 3. May 2014. https://www.genecards.org/cgi-bin/carddisp.pl?gene=ERICH3&search=264cffdfd8e64095e3fd2422d6de31ab. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 "ERICH3: vesicular association and antidepressant treatment response". Molecular Psychiatry 26 (6): 2415–2428. November 2020. doi:10.1038/s41380-020-00940-y. PMID 33230203. 
  3. ↑ 3.0 3.1 3.2 "TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics". Molecular Psychiatry 21 (12): 1717–1725. December 2016. doi:10.1038/mp.2016.6. PMID 26903268. 
  4. ↑ "Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice". The American Journal of Psychiatry 163 (1): 28–40. January 2006. doi:10.1176/appi.ajp.163.1.28. PMID 16390886. 
  5. ↑ "The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response". Translational Psychiatry 5 (4): e553. April 2015. doi:10.1038/tp.2015.47. PMID 25897834. 
  6. ↑ "Effects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study". The American Journal of Psychiatry 174 (6): 546–556. June 2017. doi:10.1176/appi.ajp.2016.16050517. PMID 28335624. 
  7. ↑ "Mass-spectrometry-based draft of the human proteome". Nature 509 (7502): 582–7. May 2014. doi:10.1038/nature13319. PMID 24870543. Bibcode: 2014Natur.509..582W. 
  8. ↑ "Quantitative Proteomic Analysis of Human Airway Cilia Identifies Previously Uncharacterized Proteins of High Abundance". Journal of Proteome Research 16 (4): 1579–1592. April 2017. doi:10.1021/acs.jproteome.6b00972. PMID 28282151. 
  9. ↑ "Assessment of Peripheral Serotonin Synthesis Using Stable Isotope-Labeled Tryptophan". Clinical Pharmacology and Therapeutics 104 (6): 1260–1267. December 2018. doi:10.1002/cpt.1087. PMID 29663345. 
  10. ↑ "ERICH3 in Primary Cilia Regulates Cilium Formation and the Localisations of Ciliary Transport and Sonic Hedgehog Signaling Proteins". Scientific Reports 9 (1): 16519. November 2019. doi:10.1038/s41598-019-52830-1. PMID 31712586. Bibcode: 2019NatSR...916519A. 
  11. ↑ 11.0 11.1 ERICH3 glutamate-rich 3 [ Homo sapiens (human) ]. https://www.ncbi.nlm.nih.gov/gene/127254. Retrieved 2015-04-30. 
  12. ↑ Skog JK, Breakefield XO, Brown D, Miranda KC, Russo LM, "Use of microvesicles in diagnosis and prognosis of medical diseases and conditions", US patent 20140194319, issued Julu 2014[|permanent dead link|dead link}}]
  13. ↑ "C1orf173". Stanford Microarray Database. 2010. http://smd.princeton.edu/cgi-bin/search/nameSearch.pl. 
  14. ↑ 2€51Stanford Microarray Database (2010). "C1orf173". http://smd.princeton.edu/cgi-bin/search/nameSearch.pl. 
  15. ↑ C1orf173 protein [Homo sapiens]. April 2015. https://www.ncbi.nlm.nih.gov/protein/AAH73916.1. 
  16. ↑ 16.0 16.1 "A comprehensive resource of interacting protein regions for refining human transcription factor networks". PLOS ONE 5 (2): e9289. February 2010. doi:10.1371/journal.pone.0009289. PMID 20195357. Bibcode: 2010PLoSO...5.9289M. 
  17. ↑ Protein of unknown function DUF4543 (IPR027870). http://www.ebi.ac.uk/interpro/entry/IPR027870. 
  18. ↑ Compute pI/Mw tool. http://web.expasy.org/compute_pi/. 
  19. ↑ Technical University of Denmark. NetPhos 2.0. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=554E2D8200006811BCB79418&wait=20. 
  20. ↑ "An equation to estimate the difference between theoretically predicted and SDS PAGE-displayed molecular weights for an acidic peptide". Scientific Reports 5 (1): 13370. August 2015. doi:10.1038/srep13370. PMID 26311515. Bibcode: 2015NatSR...513370G. 
  21. ↑ "Biology Workbench". San Diego Supercomputer Center. 2015. http://seqtool.sdsc.edu/CGI/BW.cgi. [yes|permanent dead link|dead link}}]
  22. ↑ "SOPMA SECONDARY STRUCTURE PREDICTION METHOD". Pôle BioInformatique Lyonnais. 2015. https://npsa-prabi.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsa_sopma.html. 
  23. ↑ "GOR IV SECONDARY STRUCTURE PREDICTION METHOD". Pôle BioInformatique Lyonnais. 2015. https://npsa-prabi.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsa_gor4.html. 
  24. ↑ "Phyre II". Imperial College London. 2015. http://www.sbg.bio.ic.ac.uk/phyre2/phyre2_output/b5e619da3d3563dd/summary.html. 
  25. ↑ BIOZENTRUM (2015). "SWISS-MODEL". http://swissmodel.expasy.org/interactive/jzM6zx/models/. 
  26. ↑ 26.0 26.1 26.2 "Clinic-genomic association mining for colorectal cancer using publicly available datasets". BioMed Research International 2014: 170289. 2014. doi:10.1155/2014/170289. PMID 24987669. 
  27. ↑ 27.0 27.1 "Gene expression profiles of small-cell lung cancers: molecular signatures of lung cancer". International Journal of Oncology 29 (3): 567–75. September 2006. doi:10.3892/ijo.29.3.567. PMID 16865272. 
  28. ↑ MDM2 MDM2 proto-oncogene, E3 ubiquitin protein ligase [ Homo sapiens (human) ]. April 2015. https://www.ncbi.nlm.nih.gov/gene/4193. 
  29. ↑ "Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway". Cell 119 (6): 815–29. December 2004. doi:10.1016/j.cell.2004.11.017. PMID 15607978. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Glutamate-rich_protein_3&oldid=3641419"