Biology:C18orf63

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Chromosome 18 open reading frame 63 is a protein which in humans is encoded by the C18orf63 gene.[1] This protein is not yet well understood by the scientific community. Research has been conducted suggesting that C18orf63 could be a potential biomarker for early stage pancreatic cancer and breast cancer.[2][3]

Gene

This gene is located at band 22, sub-band 3, on the long arm of chromosome 18. It is composed of 5065 base pairs spanning from 74,315,875 to 74,359,187 bp on chromosome 18.[1] The gene has a total of 14 exons.[1] C18orf63 is also known by the alias DKFZP78G0119.[4] No isoforms exist for this gene.[1]

NCBI GEO Expression Profile for C18orf63

Expression

C18orf63 has high expression in the testis.[1] The gene shows low expression in the kidneys, liver, lung, and pelvis.[5] There is no phenotype associated with this gene.[1][6]

Promoter

The promoter region for C18orf63 is 1163 bp long starting at 74,314,813 bp and ending at 74,315,975 bp.[7] The promoter ID is GXP_4417391. The presence of multiple y-box binding transcription factors and SRY transcription factor binding sites suggest that C18orf63 is involved in male sex determination.[8]

Protein

Amino acid composition of the average protein (left) and Amino acid composition of C18orf63 (right)

The C18orf63 protein is composed up of 685 amino acids and has a molecular weight of 77230.50 Da, with a predicted isoelectric point of 9.83.[1][9] No isoforms exist for this protein.[10] This protein is rich in glutamine, isoleucine, lysine, and serine when compared to the average protein, but lacks in aspartic acid and glycine.[11][12]

Structure

Partial 3D structure for C18orf63

In the predicted secondary structure for this protein there are a number of beta turns, beta strands and alpha helices. For C18orf63 48.6% of the protein is expected to form alpha helices and 28.6% of the structure is expected to be composed of beta strands.[13][14]

Domains and Motifs

Motifs and Domains for C18orf63

The protein contains one domain of unknown function, DUF 4709, spanning from the 7th amino acid to the 280th amino acid.[15] Motifs that are predicted to exist include an N-terminal motif, RxxL motif, and KEN conserving motif, which all signal for protein degradation.[16] Another motif that is predicted to exist is a Wxxx motif, which facilitates entrance of PTS1 cargo proteins into the organellar lumen, and a RVxPx motif which allows protein transport from the trans-Golgi network to the plasma membrane of the cilia.[17][18] There is also a bipartite nuclear localization signal at the end of the protein sequence.[19] There is no trans-membrane domain present, indicating that C18orf63 is not a trans-membrane protein.[20]

Post-Translational Modifications

Post-translational modifications the protein is predicted to undergo include SUMOylation, PKC and CK2 phosphorylation, N-glycosylation, amiditation, and cleavage.[21][22][23][24] There are six total PKC phosphorylation sites and 2 CK2 phosphorylation sites, 2 SUMOylation sites, and 2 N-glycosylation sites. There are no signal peptides present in this sequence.[24]

Subcellular Location

Due to the nuclear localization signal at the end of the protein sequence, C18orf63 is predicted to be nuclear. C18orf63 has also been predicted to be targeted to the mitochondria in addition to the nucleus.[25][26][27]

Homology

Orthologs

Orthologs have been found in most eukaryotes, with the exception of the class Amphibia.[10] No human paralogs exist for C18orf63.[10][28] The most distant homolog detectable is Mizuhopecten yessoensis, sharing a 37% identity with the human protein sequence. The domain of unknown function was the only homologous domain present in the protein sequence, it was found to be highly conserved in all orthologs. The table below shows some examples of various orthologs for this protein.

Table of Orthologs for C18orf63
Genus Species Common Name Accession Number Sequence Length Sequence Identity Sequence Similarity
Mammalia Galeopterus variegatus Flying lemur XP_008582575.1 677 78% 87%
Fukomys damarensis Damara mole-rat XP_019061329.1 654 70% 81%
Equus przewalskii Przewalski's horse XP_008534756.1 751 76% 83%
Loxodonta africana African bush elephant XP_023399495.1 676 73% 83%
Chinchilla lanigera Long-tailed chinchilla XP_005373135.1 679 74% 83%
Aves Corvus cornix Hooded crow XP_019138065.2 743 52% 69%
Sturnus vulgaris Common starling XP_014726419.1 742 51% 68%
Struthio camelus Southern ostrich XP_009668441.1 741 44% 62%
Phaethon lepturus White-tailed tropicbird XP_010287785.1 740 44% 60%
Nestor notabillis Kea XP_010018784.1 741 43% 60%
Reptillia Ophiophagus hannah King cobra ETE73844.1 671 55% 69%
Anolis carolinensis Carolina anole XP_008106943.1 719 48% 66%
Pogona vitticeps Central bearded dragon XP_020657479.1 676 52% 70%
Chrysemys picta Painted turtle XP_008162704.1 770 45% 60%
Fish Callorhinchus milii Australian ghostshark XP_007901438.1 738 57% 74%
Rhincodon typus Whale shark XP_020370482.1 712 41% 55%
Salmo salar Atlantic salmon XP_0140366110.1 626 43% 60%
Invertebrates Stylophora pistillata Coral XP_022802513.1 721 33% 57%
Acanthaster planci Crown of thorns starfish XP_022082271.1 750 37% 56%
Mizuhopecten yessoensis Scallop OWF48219.1 260 37% 57%
Rate of evolution for C18orf63 when compared to betaglobin, fibrinogen alpha, and cytochrome c

Rate of Evolution

C18orf63 is a mildly slow evolving protein. The protein evolves faster than Cytochorme C but slower than Betaglobin.[10]

Interacting proteins

Transcription factors of interest predicted to bind to the regulatory sequence include p53 tumor suppressors, SRY testis determining factors, Y-box binding transcription factors, and glucocorticoid responsive elements.[7] The JUN protein was found to interact with C18orf63 through anti-bait co-immunoprecipitation.[29] The JUN protein binds to the USP28 promoter in colorectal cancer cells and is involved in the activation of these cancer cells.[30][31]

Clinical significance

Mutations

A variety of missense mutations occur in the human population for this protein. In the regulatory sequence missense mutations occur at two transcription factor binding sites.[28] Transcription factors affected are glucocorticoid responsive elements and E2F-myc cell cycle regulars. There are eleven common mutations that occur that affect the protein sequence itself.[28] None of these mutations affect predicted post-translational modifications the protein sequence undergoes.

Disease association

C18orf63 has been associated with personality disorders, obesity, and type two diabetes through a genome-wide association study.[32][33][34] Currently research has not shown if C18orf63 plays a direct role in any of these diseases.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "C18orf63 chromosome 18 open reading frame 63 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/644041. 
  2. ↑ Zheng, Haiyan; Zhao, Caifeng; Qian, Meiqian; Roy, Swapan; Soherwardy, Amenah; Roy, Devjit; Kuruc, Matt (30 September 2015). "New Proteomic Workflows Combine Albumin Depletion and On- Bead Digestion, for Quantitative Cancer Serum". Biotech Support Group. Application Report (Rutgers Center for Integrative Proteomics). http://www.biotechsupportgroup.com/v/vspfiles/templates/257/pdf/New%20Proteomic%20Workflows%20Combine%20Albumin%20Depletion%20and%20On-Bead%20Digestion%20for%20Quantitative%20Cancer%20Serum%20091715.pdf. 
  3. ↑ Kuruc, Matthew (April 2016). "The Commonality of the Cancer Serum Proteome Phenotype as analyzed by LC-MS/MS, and Its Application to Monitor Dysregulated Wellness". American Association for Cancer Research Annual Meeting 2016. New Orleans LA, USA. doi:10.13140/rg.2.2.23237.65765. https://www.researchgate.net/publication/315800323. 
  4. ↑ "C18orf63 Gene". GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=C18orf63&keywords=c18orf63. 
  5. ↑ github.com/gxa/atlas/graphs/contributors, EMBL-EBI Expression Atlas development team. "Search results < Expression Atlas < EMBL-EBI" (in en). https://www.ebi.ac.uk/gxa/search?geneQuery=%5B%7B%22value%22:%22C18orf63%22,%22category%22:%22symbol%22%7D%5D&bs=%7B%22homo%20sapiens%22:%5B%22ORGANISM_PART%22%5D,%22bos%20taurus%22:%5B%22ORGANISM_PART%22%5D,%22chlorocebus%20sabaeus%22:%5B%22ORGANISM_PART%22%5D,%22equus%20caballus%22:%5B%22ORGANISM_PART%22%5D,%22macaca%20mulatta%22:%5B%22ORGANISM_PART%22%5D,%22monodelphis%20domestica%22:%5B%22ORGANISM_PART%22%5D,%22ovis%20aries%22:%5B%22ORGANISM_PART%22%5D,%22papio%20anubis%22:%5B%22ORGANISM_PART%22%5D%7D&ds=%7B%22kingdom%22:%5B%22animals%22%5D%7D#baseline. 
  6. ↑ Cosmic. "C18orf63 Gene - COSMIC". https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=C18orf63. 
  7. ↑ 7.0 7.1 "Genomatix - NGS Data Analysis & Personalized Medicine". https://www.genomatix.de/. 
  8. ↑ "SRY gene" (in en). https://ghr.nlm.nih.gov/gene/SRY. 
  9. ↑ "ExPASy - Compute pI/Mw tool" (in en-US). https://web.expasy.org/compute_pi/. 
  10. ↑ 10.0 10.1 10.2 10.3 "Protein BLAST: search protein databases using a protein query" (in en). https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE=Proteins. 
  11. ↑ EMBL-EBI. "SAPS < Sequence Statistics < EMBL-EBI" (in en). https://www.ebi.ac.uk/Tools/seqstats/saps/. 
  12. ↑ "Amino Acid Frequency". http://www.tiem.utk.edu/~gross/bioed/webmodules/aminoacid.htm. 
  13. ↑ Kumar, T. Ashok. "CFSSP: Chou & Fasman Secondary Structure Prediction Server". http://www.biogem.org/tool/chou-fasman/index.php. 
  14. ↑ "I-TASSER server for protein structure and function prediction". https://zhanglab.ccmb.med.umich.edu/I-TASSER/. 
  15. ↑ "uncharacterized protein C18orf63 [Homo sapiens - Protein - NCBI"]. https://www.ncbi.nlm.nih.gov/protein/NP_001167594.1. 
  16. ↑ "The D box meets its match". Molecular Cell 50 (5): 609–10. June 2013. doi:10.1016/j.molcel.2013.05.023. PMID 23746347. 
  17. ↑ "A novel Pex14 protein-interacting site of human Pex5 is critical for matrix protein import into peroxisomes". The Journal of Biological Chemistry 289 (1): 437–48. January 2014. doi:10.1074/jbc.M113.499707. PMID 24235149. 
  18. ↑ "Targeting of CRMP-2 to the primary cilium is modulated by GSK-3β". PLOS ONE 7 (11): e48773. 2012. doi:10.1371/journal.pone.0048773. PMID 23185275. Bibcode: 2012PLoSO...748773O. 
  19. ↑ "PSORT: a program for detecting sorting signals in proteins and predicting their subcellular localization". Trends in Biochemical Sciences 24 (1): 34–6. January 1999. doi:10.1016/S0968-0004(98)01336-X. PMID 10087920. 
  20. ↑ "Evaluation of methods for the prediction of membrane spanning regions". Bioinformatics 17 (7): 646–53. July 2001. doi:10.1093/bioinformatics/17.7.646. PMID 11448883. 
  21. ↑ "Motif Scan" (in en). https://myhits.isb-sib.ch/cgi-bin/motif_scan. 
  22. ↑ "NetAcet 1.0 Server" (in en). http://www.cbs.dtu.dk/services/NetAcet/. 
  23. ↑ "NetNGlyc 1.0 Server" (in en). http://www.cbs.dtu.dk/services/NetNGlyc/. 
  24. ↑ 24.0 24.1 "SignalP 4.0: discriminating signal peptides from transmembrane regions" (in En). Nature Methods 8 (10): 785–6. September 2011. doi:10.1038/nmeth.1701. PMID 21959131. 
  25. ↑ "Cell atlas - C18orf63 - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000206043-C18orf63/cell. 
  26. ↑ "PSORT: Protein Subcellular Localization Prediction Tool". https://www.genscript.com/psort.html. 
  27. ↑ "TargetP 1.1 Server" (in en). http://www.cbs.dtu.dk/services/TargetP/. 
  28. ↑ 28.0 28.1 28.2 "Human BLAT Search". https://genome.ucsc.edu/cgi-bin/hgBlat. 
  29. ↑ "Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes". Molecular Systems Biology 11 (1): 775. January 2015. doi:10.15252/msb.20145504. PMID 25609649. 
  30. ↑ "JUN - Transcription factor AP-1 - Homo sapiens (Human) - JUN gene & protein" (in en). https://www.uniprot.org/uniprot/P05412. 
  31. ↑ "A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype". eLife 3: e02313. March 2014. doi:10.7554/eLife.02313. PMID 24623306. 
  32. ↑ "Genome-wide association scan for five major dimensions of personality". Molecular Psychiatry 15 (6): 647–56. June 2010. doi:10.1038/mp.2008.113. PMID 18957941. 
  33. ↑ "Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population". PLOS ONE 7 (12): e51954. 2012. doi:10.1371/journal.pone.0051954. PMID 23251661. Bibcode: 2012PLoSO...751954C. 
  34. ↑ "Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels". Science 316 (5829): 1331–6. June 2007. doi:10.1126/science.1142358. PMID 17463246. Bibcode: 2007Sci...316.1331.. 



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