Glutamate-rich protein 3

ERICH3
Identifiers
AliasesERICH3, C1orf173, glutamate rich 3, Glutamate-rich protein 3
External IDsMGI: 1919095 HomoloGene: 27877 GeneCards: ERICH3
Orthologs
SpeciesHumanMouse
Entrez

127254

209601

Ensembl

ENSG00000178965

ENSMUSG00000078161

UniProt

Q5RHP9

n/a

RefSeq (mRNA)

NM_001002912

NM_175176

RefSeq (protein)

NP_001002912

n/a

Location (UCSC)Chr 1: 74.57 – 74.67 MbChr 3: 154.66 – 154.77 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Glutamate-rich protein 3, also known as Uncharacterized Protein C1orf173, is a protein encoded by the ERICH3 gene.[5] 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.[6] 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.[7] The same ERICH3 SNP was later demonstrated that was significantly associated with SSRI treatment outcomes in three independent MDD trials,[6][7] including STAR*D,[8] ISPC[9] and PReDICT.[10] 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.[6] 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.[6] ERICH3 protein was also found abundant in blood platelets[11] and cilia[12] based on the proteomic studies. Its function in platelet was thought related to plasma serotonin storage[6] because more than 99% of blood serotonin was stored in platelet[13] and ERICH3 SNPs has been associated with plasma serotonin concentration in MDD patients.[7] ERICH3 in primary cilia might regulates cilium formation and the localizations of ciliary transport.[14]

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.[15] 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.[6] 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.[16][17] C1orf173 is expressed in the brain, eye, lung, mammary gland, muscle, pituitary gland, testis, trachea, and uterus.[18]

Protein

The C1orf173 protein in humans is 1,530 amino acids (aa) in length and [19] contains two domains of unknown function, DUF4590 and DUF4543. Both DUF regions are currently uncharacterized though they are found in eukaryotes including humans.[20][21] 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.[15] 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.[6]

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.[22] 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.[23]

However, the experimental data clearly showed that ERICH3 proteins, including all three known isoforms, are localized in cytoplasma but not in nucleus.[6] 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.[6] 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.[6] 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.[24]

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.[25][26][27] In humans the tertiary structure of C1orf173 has two components that resemble ubiquitin-like 2 activating enzyme e1b and alginase.[28][29]

Protein Interactions

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

See also

  • C1orf146

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000178965 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000078161 - 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. ↑ GeneCards (May 2014). "Glutamate-Rich 3". {{cite journal}}: Cite journal requires |journal= (help)
  6. 1 2 3 4 5 6 7 8 9 10 Liu D, Zhuang Y, Zhang L, Gao H, Neavin D, Carrillo-Roa T, et al. (November 2020). "ERICH3: vesicular association and antidepressant treatment response". Molecular Psychiatry. doi:10.1038/s41380-020-00940-y. PMC 8141066. PMID 33230203. S2CID 227121990.
  7. 1 2 3 Gupta M, Neavin D, Liu D, Biernacka J, Hall-Flavin D, Bobo WV, et al. (December 2016). "TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics". Molecular Psychiatry. 21 (12): 1717–1725. doi:10.1038/mp.2016.6. PMC 5003027. PMID 26903268.
  8. ↑ Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. (January 2006). "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. doi:10.1176/appi.ajp.163.1.28. PMID 16390886.
  9. ↑ Biernacka JM, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, et al. (April 2015). "The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response". Translational Psychiatry. 5 (4): e553. doi:10.1038/tp.2015.47. PMC 4462610. PMID 25897834.
  10. ↑ Dunlop BW, Kelley ME, Aponte-Rivera V, Mletzko-Crowe T, Kinkead B, Ritchie JC, et al. (June 2017). "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. doi:10.1176/appi.ajp.2016.16050517. PMC 6690210. PMID 28335624.
  11. ↑ Wilhelm M, Schlegl J, Hahne H, Gholami AM, Lieberenz M, Savitski MM, et al. (May 2014). "Mass-spectrometry-based draft of the human proteome". Nature. 509 (7502): 582–7. Bibcode:2014Natur.509..582W. doi:10.1038/nature13319. PMID 24870543. S2CID 4467721.
  12. ↑ Blackburn K, Bustamante-Marin X, Yin W, Goshe MB, Ostrowski LE (April 2017). "Quantitative Proteomic Analysis of Human Airway Cilia Identifies Previously Uncharacterized Proteins of High Abundance". Journal of Proteome Research. 16 (4): 1579–1592. doi:10.1021/acs.jproteome.6b00972. PMC 5733142. PMID 28282151.
  13. ↑ Gehin M, Welford RW, Garzotti M, Vercauteren M, Groenen PM, Nayler O, et al. (December 2018). "Assessment of Peripheral Serotonin Synthesis Using Stable Isotope-Labeled Tryptophan". Clinical Pharmacology and Therapeutics. 104 (6): 1260–1267. doi:10.1002/cpt.1087. PMID 29663345. S2CID 4949380.
  14. ↑ Alsolami M, Kuhns S, Alsulami M, Blacque OE (November 2019). "ERICH3 in Primary Cilia Regulates Cilium Formation and the Localisations of Ciliary Transport and Sonic Hedgehog Signaling Proteins". Scientific Reports. 9 (1): 16519. Bibcode:2019NatSR...916519A. doi:10.1038/s41598-019-52830-1. PMC 6848114. PMID 31712586.
  15. 1 2 NCBI. "ERICH3 glutamate-rich 3 [ Homo sapiens (human) ]". NCBI. Retrieved 2015-04-30.
  16. ↑ US 20140194319, Skog JK, Breakefield XO, Brown D, Miranda KC, Russo LM, "Use of microvesicles in diagnosis and prognosis of medical diseases and conditions", issued Julu 2014
  17. ↑ "C1orf173". Stanford Microarray Database. 2010. Archived from the original on 2015-04-27. Retrieved 2015-04-27.
  18. ↑ 2€51Stanford Microarray Database (2010). "C1orf173". Archived from the original on 2015-04-27. Retrieved 2015-04-27.
  19. ↑ NCBI (April 2015). "C1orf173 protein [Homo sapiens]". {{cite journal}}: Cite journal requires |journal= (help)
  20. 1 2 Miyamoto-Sato E, Fujimori S, Ishizaka M, Hirai N, Masuoka K, Saito R, et al. (February 2010). "A comprehensive resource of interacting protein regions for refining human transcription factor networks". PLOS ONE. InterPro. 5 (2): e9289. Bibcode:2010PLoSO...5.9289M. doi:10.1371/journal.pone.0009289. PMC 2827538. PMID 20195357.
  21. ↑ "Protein of unknown function DUF4543 (IPR027870)". InterPro.
  22. ↑ Expasy. "Compute pI/Mw tool". {{cite journal}}: Cite journal requires |journal= (help)
  23. ↑ Technical University of Denmark. "NetPhos 2.0". {{cite journal}}: Cite journal requires |journal= (help)
  24. ↑ Guan Y, Zhu Q, Huang D, Zhao S, Jan Lo L, Peng J (August 2015). "An equation to estimate the difference between theoretically predicted and SDS PAGE-displayed molecular weights for an acidic peptide". Scientific Reports. 5 (1): 13370. Bibcode:2015NatSR...513370G. doi:10.1038/srep13370. PMC 4550835. PMID 26311515.
  25. ↑ "Biology Workbench". San Diego Supercomputer Center. 2015.
  26. ↑ "SOPMA SECONDARY STRUCTURE PREDICTION METHOD". Pôle BioInformatique Lyonnais. 2015.
  27. ↑ "GOR IV SECONDARY STRUCTURE PREDICTION METHOD". Pôle BioInformatique Lyonnais. 2015.
  28. ↑ "Phyre II". Imperial College London. 2015. Archived from the original on 2015-05-18. Retrieved 2015-05-09.
  29. ↑ BIOZENTRUM (2015). "SWISS-MODEL". Archived from the original on 2015-05-18. Retrieved 2015-05-09.
  30. 1 2 3 Liu F, Feng Y, Li Z, Pan C, Su Y, Yang R, et al. (2014). "Clinic-genomic association mining for colorectal cancer using publicly available datasets". BioMed Research International. 2014: 170289. doi:10.1155/2014/170289. PMC 4060771. PMID 24987669.
  31. 1 2 Taniwaki M, Daigo Y, Ishikawa N, Takano A, Tsunoda T, Yasui W, et al. (September 2006). "Gene expression profiles of small-cell lung cancers: molecular signatures of lung cancer". International Journal of Oncology. 29 (3): 567–75. doi:10.3892/ijo.29.3.567. PMID 16865272.
  32. ↑ NCBI (April 2015). "MDM2 MDM2 proto-oncogene, E3 ubiquitin protein ligase [ Homo sapiens (human) ]". {{cite journal}}: Cite journal requires |journal= (help)
  33. ↑ Ju BG, Solum D, Song EJ, Lee KJ, Rose DW, Glass CK, Rosenfeld MG (December 2004). "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. doi:10.1016/j.cell.2004.11.017. PMID 15607978. S2CID 2014806.
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