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C4orf21
Introduction
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. C4orf21 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
Gene
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. 12 splice variants exist for C4orf21.
Locus
C4orf21 is located on the fourth chromosome on the 4q25 position near the LARP7 gene. It is encoded for on the minus strand.
Homology and evolution
Homology and evolution
Homologous domains
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 maintenance 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
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 ΞΌ-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
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
Protein
Primary sequence
C4orf21 is 236.6 kDa.
Post-translational modifications
C4orf21 has experimentally determined phosphorylation sites at the Y38, S137, S140, S325, and S864 positions.
Secondary structure
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 and quaternary structure
C4orf21 has related structures to Upf1, a paralog. These structures have the capability to bind zinc ions and mRNA.
Function and biochemistry
Function and biochemistry
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 assembly, and pre-mRNA splicing.[3] These paralogs operate under a SPF1 RNA helicase motif.[4]
Mov10, a paralog, and probable RNA helicase is required 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
Expression
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
The transcriptional start site for c4orf21 aligns best with ATF, CREB, deltaCREB, E2F, and E2F-1 transcription factor binding sites.
Interacting proteins
Interacting proteins
C4orf21 shows predicted protein interaction with its AQR, DNA2, IGHMBP2, LOC91431, and SETX paralogs.[6]
Clinical significance
Clinical significance
C4orf21 has been previously linked to alcohol dependence[2] (where genes linked to this disorder are also linked to alcoholism and other psychological and personality disorder).[7] 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.[8][9] 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.[9][10] 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.[11]
References
References
- β “Entrez Gene: Chromosome 4 open reading frame 21”.
- β 2.0 2.1 Kalsi G, Kuo PH, Aliev F, Alexander J, McMichael O, Patterson DG, Walsh D, Zhao Z, Schuckit M, Nurnberger J, Edenberg H, Kramer J, Hesselbrock V, Tischfield JA, Vladimirov V, Prescott CA, Dick DM, Kendler KS, Riley BP (Jun 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): 2497β506. doi:10.1093/hmg/ddq112. PMCΒ 2876884. PMIDΒ 20332099.
- β Jankowsky E (Jan 2011). “RNA helicases at work: binding and rearranging”. Trends in Biochemical Sciences. 36 (1): 19β29. doi:10.1016/j.tibs.2010.07.008. PMCΒ 3017212. PMIDΒ 20813532.
- β Fairman-Williams ME, Guenther UP, Jankowsky E (Jun 2010). “SF1 and SF2 helicases: family matters”. Current Opinion in Structural Biology. 20 (3): 313β24. doi:10.1016/j.sbi.2010.03.011. PMCΒ 2916977. PMIDΒ 20456941.
- β “c4orf21”. Expression Atlas. Retrieved 16 May 2013.
- β Anon. “Predicted protein interactions between paralogs and c4orf21”. C4orf21 Gene – GeneCards. Retrieved 16 May 2013.
- β “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.
- β Nissim O, Melis M, Diaz G, Kleiner DE, 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. PMCΒ 3504149. PMIDΒ 23185381.
- β 9.0 9.1 Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S, Soboleva A (Jan 2013). “NCBI GEO: archive for functional genomics data sets–update”. Nucleic Acids Research. 41 (Database issue): D991β5. doi:10.1093/nar/gks1193. PMCΒ 3531084. PMIDΒ 23193258.
- β Philibert RA, Ryu GY, Yoon JG, Sandhu H, Hollenbeck N, Gunter T, Barkhurst A, Adams W, Madan A (Jul 2007). “Transcriptional profiling of subjects from the Iowa adoption studies”. American Journal of Medical Genetics Part B. 144B (5): 683β90. doi:10.1002/ajmg.b.30512. PMIDΒ 17342724.
- β Burdick R, Smith JL, Chaipan C, Friew Y, Chen J, Venkatachari NJ, Delviks-Frankenberry KA, Hu WS, Pathak VK (Oct 2010). “P body-associated protein Mov10 inhibits HIV-1 replication at multiple stages”. Journal of Virology. 84 (19): 10241β53. doi:10.1128/JVI.00585-10. PMCΒ 2937795. PMIDΒ 20668078.
External links
External links
- Human ZGRF1 genome location and ZGRF1 gene details page in the UCSC Genome Browser.
Further reading
Further reading
- Andersen CB, Ballut L, Johansen JS, Chamieh H, Nielsen KH, Oliveira CL, Pedersen JS, SΓ©raphin B, Le Hir H, Andersen GR (Sep 2006). “Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA”. Science. 313 (5795): 1968β72. doi:10.1126/science.1131981. PMIDΒ 16931718.
- Le Hir H, Andersen GR (Feb 2008). “Structural insights into the exon junction complex”. Current Opinion in Structural Biology. 18 (1): 112β9. doi:10.1016/j.sbi.2007.11.002. PMIDΒ 18164611.
- Schwer B (Jun 2008). “A conformational rearrangement in the spliceosome sets the stage for Prp22-dependent mRNA release”. Molecular Cell. 30 (6): 743β754. doi:10.1016/j.molcel.2008.05.003. PMCΒ 2465764. PMIDΒ 18570877.
- Lohman TM, Tomko EJ, Wu CG (May 2008). “Non-hexameric DNA helicases and translocases: mechanisms and regulation”. Nature Reviews Molecular Cell Biology. 9 (5): 391β401. doi:10.1038/nrm2394. PMIDΒ 18414490.
- Liu F, Putnam A, Jankowsky E (Dec 2008). “ATP hydrolysis is required for DEAD-box protein recycling but not for duplex unwinding”. Proceedings of the National Academy of Sciences of the United States of America. 105 (51): 20209β20214. doi:10.1073/pnas.0811115106. PMCΒ 2629341. PMIDΒ 19088201.
- Sengoku T, Nureki O, Nakamura A, Kobayashi S, Yokoyama S (Apr 2006). “Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa”. Cell. 125 (2): 287β300. doi:10.1016/j.cell.2006.01.054. PMIDΒ 16630817.
- Hirano M, Quinzii CM, Mitsumoto H, Hays AP, Roberts JK, Richard P, Rowland LP (May 2011). “Senataxin mutations and amyotrophic lateral sclerosis”. Amyotrophic Lateral Sclerosis. 12 (3): 223β7. doi:10.3109/17482968.2010.545952. PMIDΒ 21190393.
- Wang X, Han Y, Dang Y, Fu W, Zhou T, Ptak RG, Zheng YH (May 2010). “Moloney leukemia virus 10 (MOV10) protein inhibits retrovirus replication”. The Journal of Biological Chemistry. 285 (19): 14346β55. doi:10.1074/jbc.M110.109314. PMCΒ 2863248. PMIDΒ 20215113.
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