C4orf21

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Identifiers
Aliases
External IDs	GeneCards: [1]
Orthologs
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
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PubMed search	n/a	n/a
Wikidata
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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. The encoded protein of this gene has been linked with alcohol dependence. 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

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.

File:Chromosomal position of c4orf21 gene.png

Human chromosomal position of c4orf21 gene on the long arm of chromosome 4

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

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.

Sequence identity of helicase domain in paralogs

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%

File:Unrooted Phylogenetic Tree of RNA Helicase Domain in c4orf21 Paralogs.jpg

Unrooted phylogenetic tree of proteins that are paralogous to the helicase domain containing portion of c4orf21

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

Primary sequence

C4orf21 is 236.6 kDa.

File:Amino Acid Composition of c4orf21.png

Amino Acid composition of c4orf21.

Post-translational modifications

C4orf21 has experimentally determined phosphorylation sites at the Y38, S137, S140, S325, and S864 positions.

File:Post-translational modification sites of c4orf21.png

Experimentally determined post-translational modification sites in c4orf21

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.

File:C4orf21 model as proposed by Phyre 2.0. Regulator of nonsense transcripts. Hydrolase..png

Structure of C4ORF21 based upon UPF1 model. Image colored in rainbow from N to C terminus. This structure is based upon the crystal structure of the complex between 2 human nonsense mediated decay factors, upf1 and upf2, orthorhombic form.

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. These paralogs operate under a SPF1 RNA helicase motif.

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 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.

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

C4orf21 shows predicted protein interaction with its AQR, DNA2, IGHMBP2, LOC91431, and SETX paralogs.

Clinical significance

C4orf21 has been previously linked to alcohol dependence (where genes linked to this disorder are also linked to alcoholism and other psychological and personality disorder). 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. 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. 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.

External links

• Human ZGRF1 genome location and ZGRF1 gene details page in the UCSC Genome Browser.

Further reading

• Andersen CB, Ballut L, Johansen JS, Chamieh H, Nielsen KH, Oliveira CL, Pedersen JS, Séraphin 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): 1968–72. doi:10.1126/science.1131981. PMID 16931718.
• Le Hir H, Andersen GR (Feb 2008). "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.
• Schwer B (Jun 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 TM, Tomko EJ, Wu CG (May 2008). "Non-hexameric DNA helicases and translocases: mechanisms and regulation". Nature Reviews Molecular Cell Biology. 9 (5): 391–401. doi:10.1038/nrm2394. PMID 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): 20209–20214. doi:10.1073/pnas.0811115106. PMC 2629341. PMID 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): 287–300. doi:10.1016/j.cell.2006.01.054. PMID 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): 223–7. doi:10.3109/17482968.2010.545952. PMID 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): 14346–55. doi:10.1074/jbc.M110.109314. PMC 2863248. PMID 20215113.