View source for ZGRF1

{{Infobox_gene}}
'''ZGRF1''' is a [[protein]] in humans that is encoded by the ''ZGRF1'' [[gene]] that has uncharacterised function and a weight of 236.6 kDa.<ref name="entrez">{{cite web | title = Entrez Gene: Chromosome 4 open reading frame 21 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=55345 }}</ref> 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 variant]]s exist for C4orf21.

[[Image:Chromosomal position of c4orf21 gene.png|thumb|90px|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), [http://pfam.sanger.ac.uk/family/PF06839  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. [http://pfam.sanger.ac.uk/family/PF13086  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 [[Adenosine triphosphate|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.
{| class="wikitable"
|+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-AS1 (gene)|ZNFX1]] || zinc finger, NFX1-type containing 1 || 28% || 47%
|-
| [[DNA2]] || DNA replication ATP-dependent helicase/nuclease || 26% || 44%
|-
| [[Peroxisome proliferator-activated receptor gamma|PPARG]] || peroxisome proliferator-activated receptor gamma || 26% || 43%
|-
| [[HELZ2 (gene)|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|thumb|400px|none|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.
[[File:Amino Acid Composition of c4orf21.png|thumb|Amino Acid composition of c4orf21.]]

=== Post-translational modifications ===

ZGRF1 has experimentally determined [[phosphorylation]] sites at the Y38, S137, S140, S325, and S864 positions.
[[File:Post-translational modification sites of c4orf21.png|thumb|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.
[[File:C4orf21 model as proposed by Phyre 2.0. Regulator of nonsense transcripts. Hydrolase..png|thumb|none|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 (biology)|translation]], [[transcription (genetics)|transcription]], [[nonsense-mediated mRNA decay]], [[RNA decay]], [[miRNA processing]], RISC assembly, and [[pre-mRNA splicing]].<ref name="pmid20813532">{{cite journal | vauthors = Jankowsky E | title = RNA helicases at work: binding and rearranging | journal = Trends in Biochemical Sciences | volume = 36 | issue = 1 | pages = 19–29 | date = Jan 2011 | pmid = 20813532 | pmc = 3017212 | doi = 10.1016/j.tibs.2010.07.008 }}</ref> These paralogs operate under a SPF1 RNA helicase motif.<ref name="pmid20456941">{{cite journal | vauthors = Fairman-Williams ME, Guenther UP, Jankowsky E | title = SF1 and SF2 helicases: family matters | journal = Current Opinion in Structural Biology | volume = 20 | issue = 3 | pages = 313–24 | date = Jun 2010 | pmid = 20456941 | pmc = 2916977 | doi = 10.1016/j.sbi.2010.03.011 }}</ref>

[[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.<ref>{{cite web|title=c4orf21|url=http://www.ebi.ac.uk/gxa/gene?gid=Q86YA3#list.pagenum=1|publisher=Expression Atlas|accessdate=16 May 2013}}</ref>

=== Transcription factor interactions ===

The transcriptional start site for ZGRF1 aligns best with [[Activating transcription factor 2|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.<ref>{{cite web|last=Anon|title=Predicted protein interactions between paralogs and c4orf21.|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=C4orf21&search=c4orf21|publisher=C4orf21 Gene - GeneCards|accessdate=16 May 2013}}</ref>

== 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]].<ref name="pmid23185381">{{cite journal | vauthors = Nissim O, Melis M, Diaz G, Kleiner DE, Tice A, Fantola G, Zamboni F, Mishra L, Farci P | title = Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling | journal = PLOS ONE | volume = 7 | issue = 11 | pages = e49611 | year = 2012 | pmid = 23185381 | pmc = 3504149 | doi = 10.1371/journal.pone.0049611 }}</ref><ref name="Barrett_2013">{{cite journal | vauthors = 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 | title = NCBI GEO: archive for functional genomics data sets--update | journal = Nucleic Acids Research | volume = 41 | issue = Database issue | pages = D991–5 | date = Jan 2013 | pmid = 23193258 | pmc = 3531084 | doi = 10.1093/nar/gks1193 }}</ref> ZGRF1 showed significantly increased expression in those who were nicotine dependent versus a control group of non-smokers.<ref name="Barrett_2013"/><ref name="pmid17342724">{{cite journal | vauthors = Philibert RA, Ryu GY, Yoon JG, Sandhu H, Hollenbeck N, Gunter T, Barkhurst A, Adams W, Madan A | title = Transcriptional profiling of subjects from the Iowa adoption studies | journal = American Journal of Medical Genetics Part B | volume = 144B | issue = 5 | pages = 683–90 | date = Jul 2007 | pmid = 17342724 | doi = 10.1002/ajmg.b.30512 }}</ref>

A paralog of ZGRF1 was found to inhibit [[HIV-1]] [[Self-replication|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.<ref name="pmid20668078">{{cite journal | vauthors = Burdick R, Smith JL, Chaipan C, Friew Y, Chen J, Venkatachari NJ, Delviks-Frankenberry KA, Hu WS, Pathak VK | title = P body-associated protein Mov10 inhibits HIV-1 replication at multiple stages | journal = Journal of Virology | volume = 84 | issue = 19 | pages = 10241–53 | date = Oct 2010 | pmid = 20668078 | pmc = 2937795 | doi = 10.1128/JVI.00585-10 }}</ref>

== References ==
{{reflist|35em}}

==External links==
* {{UCSC gene info|ZGRF1}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Andersen CB, Ballut L, Johansen JS, Chamieh H, Nielsen KH, Oliveira CL, Pedersen JS, Séraphin B, Le Hir H, Andersen GR | title = Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA | journal = Science | volume = 313 | issue = 5795 | pages = 1968–72 | date = Sep 2006 | pmid = 16931718 | doi = 10.1126/science.1131981 }}
* {{cite journal | vauthors = Le Hir H, Andersen GR | title = Structural insights into the exon junction complex | journal = Current Opinion in Structural Biology | volume = 18 | issue = 1 | pages = 112–9 | date = Feb 2008 | pmid = 18164611 | doi = 10.1016/j.sbi.2007.11.002 }}
* {{cite journal | vauthors = Schwer B | title = A conformational rearrangement in the spliceosome sets the stage for Prp22-dependent mRNA release | journal = Molecular Cell | volume = 30 | issue = 6 | pages = 743–754 | date = Jun 2008 | pmid = 18570877 | doi = 10.1016/j.molcel.2008.05.003 | pmc=2465764}}
* {{cite journal | vauthors = Lohman TM, Tomko EJ, Wu CG | title = Non-hexameric DNA helicases and translocases: mechanisms and regulation | journal = Nature Reviews Molecular Cell Biology | volume = 9 | issue = 5 | pages = 391–401 | date = May 2008 | pmid = 18414490 | doi = 10.1038/nrm2394 }} 
* {{cite journal | vauthors = Liu F, Putnam A, Jankowsky E | title = ATP hydrolysis is required for DEAD-box protein recycling but not for duplex unwinding | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 51 | pages = 20209–20214 | date = Dec 2008 | pmid = 19088201 | pmc = 2629341 | doi = 10.1073/pnas.0811115106 }} 
* {{cite journal | vauthors = Sengoku T, Nureki O, Nakamura A, Kobayashi S, Yokoyama S | title = Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa | journal = Cell | volume = 125 | issue = 2 | pages = 287–300 | date = Apr 2006 | pmid = 16630817 | doi = 10.1016/j.cell.2006.01.054 }}
* {{cite journal | vauthors = Hirano M, Quinzii CM, Mitsumoto H, Hays AP, Roberts JK, Richard P, Rowland LP | title = Senataxin mutations and amyotrophic lateral sclerosis | journal = Amyotrophic Lateral Sclerosis | volume = 12 | issue = 3 | pages = 223–7 | date = May 2011 | pmid = 21190393 | doi = 10.3109/17482968.2010.545952 }}
* {{cite journal | vauthors = Wang X, Han Y, Dang Y, Fu W, Zhou T, Ptak RG, Zheng YH | title = Moloney leukemia virus 10 (MOV10) protein inhibits retrovirus replication | journal = The Journal of Biological Chemistry | volume = 285 | issue = 19 | pages = 14346–55 | date = May 2010 | pmid = 20215113 | doi = 10.1074/jbc.M110.109314 | pmc=2863248}}
{{refend}}
{{Commons category|C4orf21}}