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C4orf21 (Chromosome 4 open reading frame 21) is a protein in humans that is encoded by the C4orf21 gene that has uncharacterised function and a weight of 236.6 kDa.[1] The encoded protein of this gene has been linked with alcohol dependence.[2] This gene shows relatively low expression in most human tissues, with increased expression in situations of chemical dependence. These gene is orthologous to nearly all kingdoms of Eukarya. Functional domains of this protein link it to a series of helicases, most notably the AAA_12 and AAA_11 domains.
Gene
[edit]The entire gene is 97,663 base pairs long and has an unprocessed mRNA that is 6,740 nucleotides in length. It consists of 28 exons that encode for a 2104 amino acid protein.
C4orf21 is located on the fourth chromosome on the 4q25 position near the LARP7 gene. It is encoded for on the minus strand.
Homologous Domains
[edit]C4orf21 contains a DUF2439 domain (domain of unknown function), zf-GRF domain, and AAA_11 and an AAA_12 domain (ATPases associated with diverse cellular activities). DUF domains are involved in telomere maintenence and meiotic segregation. AAA_11 and AAA_12 contain a P-loop motif which are involved in conjugative transfer proteins. Other helicase domains are also present in c4orf21 orthologs.
Paralogs
[edit]There are 9 moderately-related proteins in humans that are paralogous to the ATP-dependent helicase containing domains in the C-terminus of c4orf21 after the 1612th amino acid. A majority of these proteins are in the RNA helicase family. There are no known paralogs to the large N-terminal portion of the protein.
| Paralogous Protein | Protein Name | Amino Acid Identity | Amino Acid Similarity |
|---|---|---|---|
| UPF1 | regulator of nonsense transcripts 1 | 32% | 51% |
| IGHMBP2 | immunoglobulin helicase μ-binding protein 2 | 30% | 47% |
| MOV10 | Moloney Leukemia Virus 10 | 30% | 47% |
| SETX | senataxin | 29% | 43% |
| ZNFX1 | zinc finger, NFX1-type containing 1 | 28% | 47% |
| DNA2 | DNA replication ATP-dependent helicase/nuclease | 26% | 44% |
| PPARG | peroxisome proliferator-activated receptor gamma | 26% | 43% |
| HELZ | helicase with zinc finger domain | 25% | 42% |
| AQR | intron-binding protein Aquarius | 24% | 48% |
Orthologs
[edit]Complete orthologs of the c4orf21 gene are found in mammalia. The helicase domain containing C-terminus portion of the gene is conserved across Eukarya.
Protein
[edit]Primary Sequence
[edit]C4orf21 is 236.6 kDa.
Post-translational Modifications
[edit]C4orf21 has experimentally determined phosphorylation sites at the Y38, S137, S140, S325, and S864 positions.
Secondary Structure
[edit]A weak transmembrane domain is predicted in the TMHMM server with one loop in the C-terminus of the protein prior to the helicase core. This domain contains both ends outside of a membrane.
Tertiary Domains & Quaternary Structure
[edit]C4orf21 has related structures to Upf1, a paralog. These structures have the capability to bind zinc ions and mRNA.
Function and Biochemistry
[edit]The function of c4orf21 is unknown. Given this, the paralogs to the helicase core of the gene are associated with translation, transcription, nonsense mediated mRNA decay, RNA decay, miRNA processing, RISC addembly, and pre-mRNA splicing.[3] These paralogs operate under a SPF1 RNA helicase motif.[4]
Mov10, a paralog, and probable RNA helicase is equired for RNA-mediated gene silencing by the RNA-induced silencing complex (RISC). It is also required for both miRNA-mediated translational repression and miRNA-mediated cleavage of complementary mRNAs by RISC, and for RNA-directed transcription and replication of the human hepatitis delta virus (HDV). Mov10 nteracts with small capped HDV RNAs derived from genomic hairpin structures that mark the initiation sites of RNA-dependent HDV RNA transcription.
Expression
[edit]Expression is relatively low for c4orf21 compared to other proteins. Expression of c4orf21 is slightly elevated compared to its average expression in tissue in the hematopoietic and lymphatic systems, and is above average in the brain also. Lower averages exist in liver, pharynx, and skin tissue.[5]
Transcription Factor Interactions
[edit]The transcriptional start site for c4orf21 aligns best with ATF, CREB, deltaCREB, E2F, and E2F-1 transcription factor binding sites.
Interacting Proteins
[edit]C4orf21 shows predicted protein interaction with its AQR, DNA2, IGHMBP2, LOC91431, and SETX paralogs.[6]
Clinical Significance
[edit]C4orf21 has been previously linked to alcohol dependence[7] (where genes linked to this disorder are also linked to alcoholism and other psychological and personality disorder).[8] Given this, expression of the gene in the liver and brain are particularly interesting. Upon examination of variable GEO profiles, there were many related to Hepatitis and other disorders of the liver. The best correlative studies were those in relation to liver transplant failure.[9][10] The link to alcohol dependence provides a strong connection to dependence to other chemical substances such as nicotine through analysis of lymphoblast cells. C4orf21 showed significantly increased expression in those who were nicotine dependent versus a control group of non-smokers.[11][12] Upregulation of c4orf21 was also present in certain cancer expression data sets.
A paralog of c4orf21 was found to inhibit HIV-1 Replication at multiple stages. Mov10 is involved in the biological processes of RNA-mediated gene silencing, transcription, transcription regulation and has hydrolase and helicase activity through ATP and RNA binding.[13]
References
[edit]- ^
"Entrez Gene: Chromosome 4 open reading frame 21". Retrieved 2013-05-10T12:58:38.129206-08:00.
{{cite web}}: Check date values in:|accessdate=(help) - ^ Kalsi, G (2010). "A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts". Hum. Mol. Genet. 19 (12): 2497–2506. doi:10.1093/hmg/ddq112. PMC 2876884. PMID 20332099.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Jankowsky, Eckhard (NaN undefined NaN). "RNA helicases at work: binding and rearranging". Trends in Biochemical Sciences. 36 (1): 19–29. doi:10.1016/j.tibs.2010.07.008. PMC 3017212. PMID 20813532.
{{cite journal}}: Check date values in:|date=(help) - ^ Fairman-Williams, Margaret E.; Guenther, Ulf-Peter; Jankowsky, Eckhard (NaN undefined NaN). "SF1 and SF2 helicases: family matters". Current Opinion in Structural Biology. 20 (3): 313–324. doi:10.1016/j.sbi.2010.03.011. PMC 2916977. PMID 20456941.
{{cite journal}}: Check date values in:|date=(help) - ^ "c4orf21". Expression Atlas. Retrieved 16 May 2013.
- ^ Anon. "Predicted protein interactions between paralogs and c4orf21". C4orf21 Gene - GeneCards. Retrieved 16 May 2013.
- ^ Kalsi, Gursharan; Kuo, Po-Hsiu; Aliev, Fazil; Alexander, Jeffry; McMichael, Omari; Patterson, Diana G.; Walsh, Dermot; Zhao, Zhongming; Schuckit, Marc; Nurnberger, John; Edenberg, Howard; Kramer, John; Vladimirov, Vladimir; Prescott, Carol A.; Dick, Danielle M.; Kendler, Kenneth S.; Riley, Brien P.; Kendler, K. S.; Riley, B. P. (23 March 2010). "A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts". Human Molecular Genetics. 19 (12): 2497–2506. doi:10.1093/hmg/ddq112. PMC 2876884. PMID 20332099.
- ^ "Genetic disorders linked to alcohol dependence as given be relative correlation distance". Alcohol Dependence Disease: Drugs, Articles, Genes, Clinical Trials - Malacards. Retrieved 16 May 2013.
- ^ Nissim, O.; Melis, M.; Diaz, G.; Kleiner, D. E.; Tice, A.; Fantola, G.; Zamboni, F.; Mishra, L.; Farci, P. (2012). "Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling". PLOS ONE. 7 (11): e49611. doi:10.1371/journal.pone.0049611. PMC 3504149. PMID 23185381.
- ^ Barrett, Tanya; Wilhite, Stephen E.; Ledoux, Pierre; Evangelista, Carlos; Kim, Irene F.; Tomashevsky, Maxim; Marshall, Kimberly A.; Phillippy, Katherine H.; Sherman, Patti M.; Holko, Michelle; Yefanov, Andrey; Lee, Hyeseung; Zhang, Naigong; Robertson, Cynthia L.; Serova, Nadezhda; Davis, Sean; Soboleva, Alexandra (27 November 2012). "NCBI GEO: archive for functional genomics data sets--update". Nucleic Acids Research. 41 (D1): D991–D995. doi:10.1093/nar/gks1193. PMC 3531084. PMID 23193258.
- ^ Philibert, RA (2007 Jul 5). "Transcriptional profiling of subjects from the Iowa adoption studies". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : The Official Publication of the International Society of Psychiatric Genetics. 144B (5): 683–90. doi:10.1002/ajmg.b.30512. PMID 17342724.
{{cite journal}}: Check date values in:|date=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Barrett, Tanya; Wilhite, Stephen E.; Ledoux, Pierre; Evangelista, Carlos; Kim, Irene F.; Tomashevsky, Maxim; Marshall, Kimberly A.; Phillippy, Katherine H.; Sherman, Patti M.; Holko, Michelle; Yefanov, Andrey; Lee, Hyeseung; Zhang, Naigong; Robertson, Cynthia L.; Serova, Nadezhda; Davis, Sean; Soboleva, Alexandra (27 November 2012). "NCBI GEO: archive for functional genomics data sets--update". Nucleic Acids Research. 41 (D1): D991–D995. doi:10.1093/nar/gks1193. PMC 3531084. PMID 23193258.
- ^ Burdick, Ryan; Smith, Jessica L.; Chaipan, Chawaree; Friew, Yeshitila; Chen, Jianbo; Venkatachari, Narasimhan J.; Delviks-Frankenberry, Krista A.; Hu, Wei-Shau; Pathak, Vinay K. (28 July 2010). "P Body-Associated Protein Mov10 Inhibits HIV-1 Replication at Multiple Stages". Journal of Virology. 84 (19): 10241–10253. doi:10.1128/JVI.00585-10. PMC 2937795. PMID 20668078.
Further reading
[edit]- Andersen, CB (2006 Sep 29). "Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA". Science (New York, N.Y.). 313 (5795): 1968–72. doi:10.1126/science.1131981. PMID 16931718.
{{cite journal}}: Check date values in:|date=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - Le Hir, H.; Andersen, G. R. (2008 Feb). "Structural insights into the exon junction complex". Current Opinion in Structural Biology. 18 (1): 112–9. doi:10.1016/j.sbi.2007.11.002. PMID 18164611.
{{cite journal}}: Check date values in:|date=(help) - Schwer, Beate (20 June 2008). "A Conformational Rearrangement in the Spliceosome Sets the Stage for Prp22-Dependent mRNA Release". Molecular Cell. 30 (6): 743–754. doi:10.1016/j.molcel.2008.05.003. PMC 2465764. PMID 18570877.
- Lohman, T. M.; Tomko, E. J.; Wu, C. G. (2008 May). "Non-hexameric DNA helicases and translocases: mechanisms and regulation". Nature Reviews. Molecular Cell Biology. 9 (5): 391–401. doi:10.1038/nrm2394. PMID 18414490.
{{cite journal}}: Check date values in:|date=(help) - Liu, Fei; Putnam, Andrea; Jankowsky, Eckhard (16 December 2008). "ATP hydrolysis is required for DEAD-box protein recycling but not for duplex unwinding". Proceedings of the National Academy of Sciences. 105 (51): 20209–20214. doi:10.1073/pnas.0811115106. PMC 2629341. PMID 19088201.
- Sengoku, T (2006 Apr 21). "Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa". Cell. 125 (2): 287–300. doi:10.1016/j.cell.2006.01.054. PMID 16630817.
{{cite journal}}: Check date values in:|date=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - Hirano, M.; Quinzii, C. M.; Mitsumoto, H.; Hays, A. P.; Roberts, J. K.; Richard, P.; Rowland, L. P. (2011 May). "Senataxin mutations and amyotrophic lateral sclerosis". Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 12 (3): 223–7. doi:10.3109/17482968.2010.545952. PMC 7528023. PMID 21190393.
{{cite journal}}: Check date values in:|date=(help) - Wang, X.; Han, Y.; Dang, Y.; Fu, W.; Zhou, T.; Ptak, R. G.; Zheng, Y. H. (2010 May 7). "Moloney leukemia virus 10 (MOV10) protein inhibits retrovirus replication". The Journal of Biological Chemistry. 285 (19): 14346–55. doi:10.1074/jbc.M110.109314. PMC 2863248. PMID 20215113.
{{cite journal}}: Check date values in:|date=(help)