ZGRF1

ZGRF1
Identifiers
AliasesZGRF1, C4orf21, zinc finger GRF-type containing 1
External IDsMGI: 1918893 HomoloGene: 34708 GeneCards: ZGRF1
Gene location (Human)
Chr.Chromosome 4 (human)[1]
Band4q25Start112,539,333 bp[1]
End112,636,995 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

55345

71643

Ensembl

ENSG00000138658

ENSMUSG00000051278

UniProt

Q86YA3

Q0VGT4

RefSeq (mRNA)

NM_001099776
NM_018392
NM_138698
NM_001350397

NM_197997

RefSeq (protein)

NP_060862
NP_001337326

NP_932114

Location (UCSC)Chr 4: 112.54 – 112.64 MbChr 3: 127.55 – 127.62 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ZGRF1 is a protein in humans that is encoded by the ZGRF1 gene that has uncharacterised function and a weight of 236.6 kDa.[5] This gene shows relatively low expression in most human tissues, with increased expression in situations of chemical dependence. ZGRF1 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.

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

Locus

ZGRF1 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

ZGRF1 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 ProteinProtein NameAmino Acid IdentityAmino Acid Similarity
UPF1regulator of nonsense transcripts 132%51%
IGHMBP2immunoglobulin helicase μ-binding protein 230%47%
MOV10Moloney Leukemia Virus 1030%47%
SETXsenataxin29%43%
ZNFX1zinc finger, NFX1-type containing 128%47%
DNA2DNA replication ATP-dependent helicase/nuclease26%44%
PPARGperoxisome proliferator-activated receptor gamma26%43%
HELZhelicase with zinc finger domain25%42%
AQRintron-binding protein Aquarius24%48%
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

ZGRF1 is 236.6 kDa.

Amino Acid composition of c4orf21.

Post-translational modifications

ZGRF1 has experimentally determined phosphorylation sites at the Y38, S137, S140, S325, and S864 positions.

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

ZGRF1 has related structures to Upf1, a paralog. These structures have the capability to bind zinc ions and mRNA.

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 ZGRF1 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.[6] These paralogs operate under a SPF1 RNA helicase motif.[7]

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.[8]

Transcription factor interactions

The transcriptional start site for ZGRF1 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.[9]

Clinical significance

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.[10][11] ZGRF1 showed significantly increased expression in those who were nicotine dependent versus a control group of non-smokers.[11][12]

A paralog of ZGRF1 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

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000138658 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000051278 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ "Entrez Gene: Chromosome 4 open reading frame 21".
  6. ↑ Jankowsky E (Jan 2011). "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.
  7. ↑ Fairman-Williams ME, Guenther UP, Jankowsky E (Jun 2010). "SF1 and SF2 helicases: family matters". Current Opinion in Structural Biology. 20 (3): 313–24. doi:10.1016/j.sbi.2010.03.011. PMC 2916977. PMID 20456941.
  8. ↑ "c4orf21". Expression Atlas. Retrieved 16 May 2013.
  9. ↑ Anon. "Predicted protein interactions between paralogs and c4orf21". C4orf21 Gene - GeneCards. Retrieved 16 May 2013.
  10. ↑ 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. PMC 3504149. PMID 23185381.
  11. 1 2 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): D991–5. doi:10.1093/nar/gks1193. PMC 3531084. PMID 23193258.
  12. ↑ 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): 683–90. doi:10.1002/ajmg.b.30512. PMID 17342724.
  13. ↑ 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): 10241–53. doi:10.1128/JVI.00585-10. PMC 2937795. PMID 20668078.

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.
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