ZCCHC18

Last updated
ZCCHC18
Identifiers
Aliases ZCCHC18 , PNMA7B, SIZN2, zinc finger CCHC-type containing 18
External IDs MGI: 1914245 HomoloGene: 121722 GeneCards: ZCCHC18
Orthologs
SpeciesHumanMouse
Entrez

644353

66995

Ensembl

n/a

ENSMUSG00000031428

UniProt

P0CG32

Q8VD24

RefSeq (mRNA)

NM_001143978

RefSeq (protein)

NP_001137450

Location (UCSC)n/a Chr X: 135.89 – 135.9 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Zinc finger CCHC-type containing 18 (ZCCHC18) is a protein that in humans is encoded by ZCCHC18 gene. It is also known as Smad-interacting zinc finger protein 2 (SIZN2), para-neoplastic Ma antigen family member 7b (PNMA7B), and LOC644353. [4] [5] Other names such as zinc finger, CCHC domain containing 12 pseudogene 1, P0CG32, ZCC18_HUMAN had been used to describe this protein.

Contents

ZCCHC18 belongs to the ZCCHC12 family or para-neoplastic Ma (PNMA). It is a ligand-dependent nuclear receptor transcription coactivator. Its zinc finger domain is CCHC which binds to zinc ion (see protein section for detail information on CCHC motif). [6]

It is worthwhile to mention that in mammals, PNMA is derived from Ty3/Gypsy long terminal repeat (LTR) retrotransposons and PNMA family encodes the Gag-like protein. [7] Although the full functions remain unknown, most PNMA genes are expressed in brains of macaques and mice. [8] PNMA1, 2 and 3 were found in the serum of patients with paraneoplastic neurological disorders. The family also includes modulator of apoptosis 1, having a role in death receptor-dependent apoptosis. [9]

Gene

Location

ZCCHC18 gene locates at the long arm of X chromosome, loci position Xq22.2. This gene contains 3 exons and 2 distinct gt-ag introns, being transcribed into 3 alternatively spliced mRNAs. However, only one spliced mRNA (NM_001143978.2, 2951 bp) putatively encodes a 403 amino acid protein, whereas the others does not encode proteins. [10]

Gene Neighborhood

Nearby genes include SLC25A53 (on the negative strand) (about 8,000 base pairs (bps) upstream) and FAM199X (on the positive strand) (about 50,800 bps downstream). [6]

Expression

ZCCHC18 ubiquitously expresses in ovary, brain (cerebellum), endometrium, lymph node, spleen and 22 other tissues in human and other species. [11] Based on RNA-Seq expression data from GTEx (53 tissues from 570 donors), highest median expression is in brain—cerebellum (4.74 RPKM) whereas the total median expression of 67.54 RPKM. [12]

Promoter

Possible transcription binding sites is analyzed by Genomatix, [13] listed in the table below:

Possible transcription factors and binding sites of ZCCHC18 identified by Genomatix
Matrix FamilyDetailed Family InformationAnchor positionStrandMatrix sim.Sequence
V$AP1RMAF and AP1 related factors1225-0.996gcacggcgtcAGCAgctcggacgca
V$MZF1Myeloid zinc finger 1 factors1040-0.995agGGGGaagcg
V$ZF02C2H2 zinc finger transcription factors 21916-0.993caccccgCCCCcgacacccaaca
V$CAATCCAAT binding factors1368-0.991gcggCCAAtcagcgg
V$SORYSOX/SRY-sex/testis determining and related HMG box factors307+0.989gggtcaCAAAgggctgtcgaaat
V$ZFHXTwo-handed zinc finger homeodomain transcription factors1029+0.988acgctGTTTcccc
V$ZTREZinc transcriptional regulatory element503-0.984gagGGAGggggtgagga
V$ZTREZinc transcriptional regulatory element2165+0.984gcgGGAGggcaggaggc
V$NEURNeuroD, Beta2, HLH domain774+0.982ctccCATCtggcttt
V$MIZ1Myc-interacting Zn finger protein 1480+0.981tcagcCCTCtc
V$IKRSIkaros zinc finger family1483+0.98ccttGGGAaccgt
V$CEBPCcaat/Enhancer Binding Protein713+0.979tcatcTGTGaaatgg
V$GATAGATA binding factors724+0.974tggaGATAatggt
O$INRECore promoter initiator elements1407+0.972tcTCAGtcgcc
V$AP2FActivator protein 21281-0.936ctgGCCGgcgggccg
V$MAZFMyc associated zinc fingers1126+0.904cccgGAGGagagc

Homology

Orthologs

Orthologs of ZCCHC18 can be found in most Chordata (Mammalia, Amphibian, Reptilian, Osteichthyes, but not in Arthropod, Aves, Chondrichthyes), Echinoderm, and Cnidarian but not in Fungus, Plant, Ciliates, Archaea, nor Bacteria.

Paralogs

Eight possible paralogs of ZCCHC18 were identified in Homo sapiens .

Gene NameAccessionCoverageE-ValueSequence Identity %
PNMA7A (ZCCHC12) NP_776159.1 99%084%
PNMA3 NP_001269464.1 91%4.00E-4029%
PNMA1 NP_006020.4 45%3.00E-3943%
PNMA5 NP_443158.1 47%4.00E-3941%
PNMA2 NP_009188.1 48%5.00E-3941%
PNMA6A (PNMA6C) NP_116271.3 52%6.00E-2738%
PNMA6E NP_001338223.1 48%4.00E-2136%
PNMA6F (PNMA6BL) NP_001341909.1 54%1.00E-1833%

Note: PNMA4 (aliases: modulator of apoptosis 1, MOAP1) does not appear to be similar to ZCCHC18 (the identity and similarity between ZCCHC18 and MOAP1 are 15% and 32.1%, respectively).

Transcript

Splice Variants

Alternative splicing of ZCCHC18 mRNAs in Homo sapiens Alternative splicing of ZCCHC18 mRNAs in Homo sapiens.png
Alternative splicing of ZCCHC18 mRNAs in Homo sapiens

Including 5’-UTR and 3’-UTR, ZCCHC18 spans from chrX:104,112,526-104,115,846 with a total of 3,321 base pairs (bps) (5’-UTR: 1206 bps and 3’-UTR: 523 bps). It contains 3 exons and 2 distinct gt-ag introns, being transcribed into 3 alternatively spliced mRNAs. However, only one spliced mRNA (NM_001143978.2, 2951 bps) putatively encodes a protein with 403 amino acids (coding region: hg38 chrX:104,114,112-104,115,323, total 1,212 bps), whereas others do not encode proteins. [6] [15] [16]

Comparing to human ZCCHC18 mRNA which there are 3 isoforms, there are 7 isoforms of Zcchc18 in mouse (Mus musculus), and no isoform in cat (Felis catus) and leopard (Panthera pardus).

Protein

ZCCHC18 is a human protein with 403 amino acids in length and has a predicted molecular weight of 45,160 daltons. Its basal isoelectric point is 7.02 (unphosphorylated state), and isoelectric point decreased with increased number of residues being phosphorylated. The common sequences of ZCCHC18 include KRED and LVIFM. It is generally electroneutral (there are no positive or negative charge clusters or segments) with no high hydrophobic segments.

Secondary Structure

ZCCHC18 secondary structure ZCCHC18 secondary structure.png
ZCCHC18 secondary structure

Secondary structure prediction of a not well-characterized protein can be performed by using PRBI database, [17] Phyre2, [14] and I-TASSER. [18] The secondary structure prediction of ZCCHC18 was analyzed by Phyre2.

Tertiary Structure

The tertiary structure was predicted by I-TASSER [18] in the attempt to optimize C-score, TM-score, and cluster density. The predicted ZCCHC18 tertiary structure is shown in the figure..

Post-Translational Modifications

ZCCHC18 tertiary structure ZCCHC18 tertiary structure.png
ZCCHC18 tertiary structure
Predicted post translation modifications of human ZCCHC18 Predicted post translation modification of human ZCCHC18.png
Predicted post translation modifications of human ZCCHC18

The predicted post-translational modifications (PTMs) is obtained by using Prosite, [19] and many other tools. [20] [21] [22] [23] [24] [25] [26] The key post translation modifications are summarized here.

Subcellular Localization

ZCCHC18 primary locates in the nucleus (appearance to be nuclear speck, a discrete extra-nucleolar subnuclear domain, under immunofluorescence microscopy). [27]

Function

Amino acid sequence of zinc finger CCHC-type in retroviral nucleocapsid proteins Amino acid sequence of ZCCHC18.png
Amino acid sequence of zinc finger CCHC-type in retroviral nucleocapsid proteins

Although the exact function of ZCCHC18 is still not fully known, the basic amino acid sequence of the zinc finger (Znf) CCHC-type protein can be well characterized as conservatively spaced cysteine and histidine. [7] The Cys and His residues is completely conserved at position 1 (Cys), 4 (Cys), 9 (His), and 14 (Cys) [as the first Cys of the sequence labeled as Cys (1)]. Conservatively substituted glycines occur at position 5 and 8, and aromatic or hydrophobic amino acids are at positions 2 (or 3) and 10. This motif is often expressed as Cys-X2-Cys-X4-His-X4-Cys.

The structure of zinc finger domains enables the protein to make tandem contact with target molecules through multiple finger-like protrusions. These domains can bind to zinc or other metals such as iron, or even no metal (stabilizing through salt bridges). [28] The exact mechanism for how the Znf domain of ZCCHC18 work is still unknown.

Interacting Proteins

ZCCHC18 can possibly interact with the intracellular domain of EGFR. This report was based on the two protein-protein interaction (PPI) approaches, the membrane yeast two-hybrid (MYTH) and the mammalian membrane two-hybrid (MMTH), to map the PPIs between human receptor tyrosine kinases (RTKs) and phosphatases. [29]

Clinical Significance

Disease Association

RNA Expression of ZCCHC18 in different cancer types from TCGA dataset ZCCHC18 TCGA Data.png
RNA Expression of ZCCHC18 in different cancer types from TCGA dataset

By examining RNA-seq data from The Cancer Genome Atlas (TCGA), [30] glioma has enhanced RNA expression (median 1.9 FPKM [Fragments Per Kilobase of exon per Million reads]) whereas other cancer types only have minimal expression (median expression level lower than 0.5 FPKM). In terms of the ZCCHC18 protein expression, squamous and basal cell carcinomas, and cases of urothelial cancers exhibited moderate to strong cytoplasmic immunoreactivity. Remaining cancer cells were weakly stained or negative. While interrogating 4440 tumor samples from 15 cancer types from TCGA, [13] the analysis showed a vary protein mutation frequency in different cancer types. ZCCHC18 mutation happened frequently in endometrial cancer (~ 2.4%), followed by bladder cancer (~0.8%), head/neck carcinoma (~0.4%), ovarian cancer (~0.4%), and breast cancer (<0.2%).

Genetic Testing

As of May 2021, Fulgent Genetics was the only commercial company that provided the genetic testing for deletion or duplication of ZCCHC18 through sequence analysis of the entire coding region (Next-Generation Sequencing) for possible diseases caused by mutations on this particular gene that are inherited from a parent's genome. However, the clinical validity and utility have not been proven yet. [31]

Related Research Articles

<span class="mw-page-title-main">Chromosome 1</span> Human chromosome

Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which are the basic units of information for DNA. It represents about 8% of the total DNA in human cells.

<span class="mw-page-title-main">Chromosome 13</span> Human chromosome

Chromosome 13 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 13 spans about 113 million base pairs and represents between 3.5 and 4% of the total DNA in cells.

<span class="mw-page-title-main">Chromosome 3</span> Human chromosome

Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans 201 million base pairs and represents about 6.5 percent of the total DNA in cells.

<span class="mw-page-title-main">Chromosome 4</span> Human chromosome

Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 193 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells.

<span class="mw-page-title-main">Chromosome 8</span> Human chromosome

Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 146 million base pairs and represents between 4.5 and 5.0% of the total DNA in cells.

<span class="mw-page-title-main">Chromosome 9</span> Human chromosome

fChromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 150 million base pairs of nucleic acids and represents between 4.0 and 4.5% of the total DNA in cells.

<span class="mw-page-title-main">Chromosome 12</span> Human chromosome

Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs and represents between 4 and 4.5 percent of the total DNA in cells.

<span class="mw-page-title-main">Chromosome 18</span> Human chromosome

Chromosome 18 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 18 spans about 80 million base pairs and represents about 2.5 percent of the total DNA in cells.

<span class="mw-page-title-main">Chromosome 20</span> Human chromosome

Chromosome 20 is one of the 23 pairs of chromosomes in humans. Chromosome 20 spans around 66 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells. Chromosome 20 was fully sequenced in 2001 and was reported to contain over 59 million base pairs. Since then, due to sequencing improvements and fixes, the length of chromosome 20 has been updated to just over 66 million base pairs.

<span class="mw-page-title-main">CZIB</span> Protein-coding gene in the species Homo sapiens

CZIB is a gene in the human genome that encodes the protein CXXC motif containing zinc binding protein. CZIB was previously referred to as C1orf123.

<span class="mw-page-title-main">CCDC94</span> Protein found in humans

Coiled-coil domain containing 94 (CCDC94) is a protein that in humans is encoded by the CCDC94 gene. The CCDC94 protein contains a coiled-coil domain, a domain of unknown function (DUF572), an uncharacterized conserved protein (COG5134), and lacks a transmembrane domain.

<span class="mw-page-title-main">C8orf48</span> Protein-coding gene in the species Homo sapiens

C8orf48 is a protein that in humans is encoded by the C8orf48 gene. C8orf48 is a nuclear protein specifically predicted to be located in the nuclear lamina. C8orf48 has been found to interact with proteins that are involved in the regulation of various cellular responses like gene expression, protein secretion, cell proliferation, and inflammatory responses. This protein has been linked to breast cancer and papillary thyroid carcinoma.

The coiled-coil domain containing 142 (CCDC142) is a gene which in humans encodes the CCDC142 protein. The CCDC142 gene is located on chromosome 2, spans 4339 base pairs and contains 9 exons. The gene codes for the coiled-coil domain containing protein 142 (CCDC142), whose function is not yet well understood. There are two known isoforms of CCDC142. CCDC142 proteins produced from these transcripts range in size from 743 to 665 amino acids and contain signals suggesting protein movement between the cytosol and nucleus. Homologous CCDC142 genes are found in many animals including vertebrates and invertebrates but not fungus, plants, protists, archea, or bacteria. Although the function of this protein is not well understood, it contains a coiled-coil domain and a RINT1_TIP1 motif located within the coiled-coil domain.

<span class="mw-page-title-main">C4orf51</span> Protein-coding gene in the species Homo sapiens

Chromosome 4 open reading frame 51 (C4orf51) is a protein which in humans is encoded by the C4orf51 gene.

Transmembrane protein 151A, also known as TMEM151A, is a protein that is encoded by the TMEM151A gene.

<span class="mw-page-title-main">ZNF337</span> Protein-coding gene in the species Homo sapiens

ZNF337, also known as zinc finger protein 337, is a protein that in humans is encoded by the ZNF337 gene. The ZNF337 gene is located on human chromosome 20 (20p11.21). Its protein contains 751 amino acids, has a 4,237 base pair mRNA and contains 6 exons total. In addition, alternative splicing results in multiple transcript variants. The ZNF337 gene encodes a zinc finger domain containing protein, however, this gene/protein is not yet well understood by the scientific community. The function of this gene has been proposed to participate in a processes such as the regulation of transcription (DNA-dependent), and proteins are expected to have molecular functions such as DNA binding, metal ion binding, zinc ion binding, which would be further localized in various subcellular locations. While there are no commonly associated or known aliases, an important paralog of this gene is ZNF875

<span class="mw-page-title-main">C7orf50</span> Mammalian protein found in Homo sapiens

C7orf50 is a gene in humans that encodes a protein known as C7orf50. This gene is ubiquitously expressed in the kidneys, brain, fat, prostate, spleen, among 22 other tissues and demonstrates low tissue specificity. C7orf50 is conserved in chimpanzees, Rhesus monkeys, dogs, cows, mice, rats, and chickens, along with 307 other organisms from mammals to fungi. This protein is predicted to be involved with the import of ribosomal proteins into the nucleus to be assembled into ribosomal subunits as a part of rRNA processing. Additionally, this gene is predicted to be a microRNA (miRNA) protein coding host gene, meaning that it may contain miRNA genes in its introns and/or exons.

<span class="mw-page-title-main">C1orf94</span> Protein-coding gene in the species Homo sapiens

Chromosome 1 Opening Reading Frame 94 or C1orf94 is a protein in human coded by the C1orf94 gene. The function of this protein is still poorly understood.

<span class="mw-page-title-main">C6orf136</span> Protein-coding gene in the species Homo sapiens

C6orf136 is a protein in humans encoded by the C6orf136 gene. The gene is conserved in mammals, mollusks, as well some porifera. While the function of the gene is currently unknown, C6orf136 has been shown to be hypermethylated in response to FOXM1 expression in Head Neck Squamous Cell Carcinoma (HNSCC) tissue cells. Additionally, elevated expression of C6orf136 has been associated with improved survival rates in patients with bladder cancer. C6orf136 has three known isoforms.

<span class="mw-page-title-main">ZNF548</span> Protein-coding gene in the species Homo sapiens

Zinc Finger Protein 548 (ZNF548) is a human protein encoded by the ZNF548 gene which is located on chromosome 19. It is found in the nucleus and is hypothesized to play a role in the regulation of transcription by RNA Polymerase II. It belongs to the Krüppel C2H2-type zinc-finger protein family as it contains many zinc-finger repeats.

References

  1. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031428 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "ZCCHC18 Gene". GeneCards.
  5. ↑ "Gene: ZCCHC18 (ENSG00000166707) - Summary - Homo sapiens - Ensembl genome browser 91". useast.ensembl.org. Retrieved 2018-02-22.
  6. 1 2 3 "Human Gene ZCCHC18 (ENST00000611638.4) Description and Page Index". genome.ucsc.edu. Retrieved 2018-04-30.
  7. 1 2 Summers MF (January 1991). "Zinc finger motif for single-stranded nucleic acids? Investigations by nuclear magnetic resonance". Journal of Cellular Biochemistry. 45 (1): 41–8. doi:10.1002/jcb.240450110. PMID   2005183. S2CID   45192514.
  8. ↑ Takaji M, Komatsu Y, Watakabe A, Hashikawa T, Yamamori T (December 2009). "Paraneoplastic antigen-like 5 gene (PNMA5) is preferentially expressed in the association areas in a primate specific manner". Cerebral Cortex. 19 (12): 2865–79. doi:10.1093/cercor/bhp062. PMC   2774394 . PMID   19366867.
  9. ↑ Iwasaki S, Suzuki S, Pelekanos M, Clark H, Ono R, Shaw G, Renfree MB, Kaneko-Ishino T, Ishino F (October 2013). "Identification of a novel PNMA-MS1 gene in marsupials suggests the LTR retrotransposon-derived PNMA genes evolved differently in marsupials and eutherians". DNA Research. 20 (5): 425–36. doi:10.1093/dnares/dst020. PMC   3789554 . PMID   23704700.
  10. ↑ "1000 Genomes Browser". www.ncbi.nlm.nih.gov. Retrieved 2018-02-22.
  11. ↑ "ZCCHC18 zinc finger CCHC-type containing 18 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-30.
  12. ↑ "Gene expression for ZCCHC18 (ENSG00000166707.6)". GTEx Portal. 2018-04-30.
  13. 1 2 "Genomatix: Human ZCCHC18". www.genomatix.de. Retrieved 2018-05-10.
  14. 1 2 3 Kelley, Lawrence. "PHYRE2 Protein Fold Recognition Server". www.sbg.bio.ic.ac.uk. Retrieved 2018-05-10.
  15. ↑ Thierry-Mieg, Danielle; Thierry-Mieg, Jean. "AceView: Gene:ZCCHC18, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView". www.ncbi.nlm.nih.gov. Retrieved 2018-04-30.
  16. ↑ "Gene: ZCCHC18 (ENSG00000166707) - Summary - Homo sapiens - Ensembl genome browser 92". useast.ensembl.org. Retrieved 2018-04-30.
  17. ↑ UCBL, Institut de Biologie et Chimie des Proteines - UMR5086 - CNRS -. "NPS@ : GOR4 secondary structure prediction". npsa-prabi.ibcp.fr. Retrieved 2018-05-10.{{cite web}}: CS1 maint: numeric names: authors list (link)
  18. 1 2 3 "I-TASSER server for protein structure and function prediction". zhanglab.ccmb.med.umich.edu. Retrieved 2018-05-10.
  19. ↑ "Prosite: Human ZCCHC18".
  20. ↑ "NetAcet 1.0 Server". www.cbs.dtu.dk. Retrieved 2018-05-10.
  21. ↑ "SUMOplot™ Analysis Program | Abgent". www.abgent.com. Retrieved 2018-05-10.
  22. ↑ "GPS-SUMO: Prediction of SUMOylation Sites & SUMO-interaction Motifs". sumosp.biocuckoo.org. Retrieved 2018-05-10.
  23. ↑ "CSS-Palm - Palmitoylation Site Prediction". csspalm.biocuckoo.org. Retrieved 2018-05-10.
  24. ↑ ":::BDM-PUB - Prediction of Ubiquitination Sites with Bayesian Discriminant Method:::". bdmpub.biocuckoo.org. Retrieved 2018-05-10.
  25. ↑ "ExPASy - Sulfinator". web.expasy.org. Retrieved 2018-05-10.
  26. ↑ "MYR Prediction Server". mendel.imp.ac.at. Retrieved 2018-05-10.
  27. 1 2 "ZCCHC18 - Zinc finger CCHC domain-containing protein 18 - Homo sapiens (Human) - ZCCHC18 gene & protein". www.uniprot.org. Retrieved 2018-05-10.
  28. ↑ EMBL-EBI, InterPro. "Zinc finger, CCHC-type (IPR001878) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2018-02-22.
  29. ↑ Yao Z, Darowski K, St-Denis N, Wong V, Offensperger F, Villedieu A, Amin S, Malty R, Aoki H, Guo H, Xu Y, Iorio C, Kotlyar M, Emili A, Jurisica I, Neel BG, Babu M, Gingras AC, Stagljar I (January 2017). "A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome". Molecular Cell. 65 (2): 347–360. doi:10.1016/j.molcel.2016.12.004. PMC   5663465 . PMID   28065597.
  30. ↑ "Search: ZCCHC18 - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2018-05-10.
  31. ↑ "ZCCHC18 - Tests - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-02-22.
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