ZCCHC18

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ZCCHC18
Identifiers
AliasesZCCHC18, PNMA7B, SIZN2, zinc finger CCHC-type containing 18
External IDsMGI: 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/aChr X: 135.89 – 135.9 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/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.

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 Family Detailed Family Information Anchor position Strand Matrix sim. Sequence
V$AP1R MAF and AP1 related factors 1225 - 0.996 gcacggcgtcAGCAgctcggacgca
V$MZF1 Myeloid zinc finger 1 factors 1040 - 0.995 agGGGGaagcg
V$ZF02 C2H2 zinc finger transcription factors 2 1916 - 0.993 caccccgCCCCcgacacccaaca
V$CAAT CCAAT binding factors 1368 - 0.991 gcggCCAAtcagcgg
V$SORY SOX/SRY-sex/testis determining and related HMG box factors 307 + 0.989 gggtcaCAAAgggctgtcgaaat
V$ZFHX Two-handed zinc finger homeodomain transcription factors 1029 + 0.988 acgctGTTTcccc
V$ZTRE Zinc transcriptional regulatory element 503 - 0.984 gagGGAGggggtgagga
V$ZTRE Zinc transcriptional regulatory element 2165 + 0.984 gcgGGAGggcaggaggc
V$NEUR NeuroD, Beta2, HLH domain 774 + 0.982 ctccCATCtggcttt
V$MIZ1 Myc-interacting Zn finger protein 1 480 + 0.981 tcagcCCTCtc
V$IKRS Ikaros zinc finger family 1483 + 0.98 ccttGGGAaccgt
V$CEBP Ccaat/Enhancer Binding Protein 713 + 0.979 tcatcTGTGaaatgg
V$GATA GATA binding factors 724 + 0.974 tggaGATAatggt
O$INRE Core promoter initiator elements 1407 + 0.972 tcTCAGtcgcc
V$AP2F Activator protein 2 1281 - 0.936 ctgGCCGgcgggccg
V$MAZF Myc associated zinc fingers 1126 + 0.904 cccgGAGGagagc

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 Name Accession Coverage E-Value Sequence Identity %
PNMA7A (ZCCHC12) NP_776159.1 99% 0 84%
PNMA3 NP_001269464.1 91% 4.00E-40 29%
PNMA1 NP_006020.4 45% 3.00E-39 43%
PNMA5 NP_443158.1 47% 4.00E-39 41%
PNMA2 NP_009188.1 48% 5.00E-39 41%
PNMA6A (PNMA6C) NP_116271.3 52% 6.00E-27 38%
PNMA6E NP_001338223.1 48% 4.00E-21 36%
PNMA6F (PNMA6BL) NP_001341909.1 54% 1.00E-18 33%

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[14]

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[14]

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[18]
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

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[27]

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]

References

  1. ^ a b c 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. ^ a b c "Human Gene ZCCHC18 (ENST00000611638.4) Description and Page Index". genome.ucsc.edu. Retrieved 2018-04-30.
  7. ^ a b 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. ^ a b "Genomatix: Human ZCCHC18". www.genomatix.de. Retrieved 2018-05-10.
  14. ^ a b c 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. ^ a b c "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. ^ a b "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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