C3orf67 Explained

Chromosome 3 open reading frame 67 or C3orf67 is a protein that in humans is encoded by the gene C3orf67.^{[1] [2]} The function of C3orf67 is not yet fully understood.

Gene

C3orf67 is located at 3p14.2 on the reverse strand ranging from 58716417 to 59050045 base pairs.^{[3] [1]} The accession number is NP_001338459.1.^[4]

Protein

Primary sequence and isoforms

The coding sequence is 402-2681 base pairs of 3135 base pairs, making up 759 amino acids.^[1] C3orf67 has six validated isoforms.^[1] Isoform one is the most complete with 16 exons. C3orf67 weighs 84.35 kilodaltons.^[5]

Domains and motifs

There are three functional domains identified for C3orf67^[6]

• DUF667
• CM_mono2
• OCRE

Post-translational modifications

Several post-translational modifications have been predicted for C3orf67 in conserved regions using various bioinformatic prediction tools^{[7] [8] [9] [10] [11] [12] [13] [14]}

• Two nuclear export signals
• Three sumoylation sites
• Two o-glycosylation sites
• One phosphorylation site
• One tyrosine sulfation site

Secondary structure

The beginning of C3orf67 is predicted to consist of a series of beta strands and a couple alpha helices that coincide with the DUF667 domain. There are also alpha helices predicted in regions that correspond to the CM_mono2 and OCRE domains.^{[15] [16] [17]}

Tertiary structure

The DUF667 region is predicted to form a tube-like structure from a series of beta sheets.

Homology and Evolution

Paralogs

There are no known paralogs of C3orf67.

Orthologs

Orthologs have been identified for C3orf67 in species ranging from fungus, plants, hemichordates, parasites, fish, reptiles, birds, invertebrates, and mammals.

Species

Common Name	Date of Divergence (MYA)	Accession Number	Sequence Length (aa)	% Identity
Orbicella faveolata	Mountainous star coral	824	XP_020630732.1 / XP_020630739.1	849	32.20%
Exaiptasia pallida	Pale anemone	824	XP_020899564.1	797	32.00%
Acanthaster planci	Crown-of-thorns starfish	684	XP_022107809.1	976	31.60%
Stylophora pistillata	Smooth cauliflower coral	824	XP_022782397.1	825	30.80%
Crassostrea gigas	Pacific oyster	797	XP_011453705.1	950	29.50%
Lingula anatina	Lamp shell	797	XP_013404893.1	1077	29.30%
Octopus bimaculoides	California two-spotted octopus	797	XP_014778712.1	902	29.10%
Saccoglossus kowalevskii	Acorn worm	684	XP_006821003.1	596	23.30%
Amphimedon queenslandica	Sponge	951.8	XP_011402616.1	508	22.70%

Distant homologs

Species

Common Name	Date of Divergence (MYA)	Accession Number	Sequence Length (aa)	% Identity
Trichinella spiralis	Trichina worm	797	XP_003374081.1	393	12.60%
Spizellomyces punctatus	Unknown	1105	XP_016608387.1	183	8.20%
Selaginella moellendorffii	Spikemoss	1496	XP_002989784.1	209	6.00%

Expression

Promoter

The promoter is well conserved across humans, gibbons, baboons, orangutans, cats, squirrels, alpacas, rabbits and mice.^[18] There are several high quality transcription factor binding sites. There are also several stem-loop structures that are predicted to be formed in the promoter region, some of which overlap with transcription factor binding sites.^[19]

Expression

C3orf67 is prominently expressed in the liver, tonsils, trachea, ovaries, testis, placenta, and colon. In other tissues it is expressed at low levels.^[20] An increase in expression has been linked to small cell lung cancer.^[21]

Function

The protein has been identified as one of seventeen (17) genes that may play a novel role in the intersection of tumor promotion and DNA-damaging stress and may be linked to carcinogenesis.^[22]

Interacting Proteins

Transcription factors

There are three notable transcription factors that are known to be involved in the regulation of cell growth or immune responses:

• V$SMAD3.01^[23]
  • Smad3 is a transcription factor involved in TGF-beta signaling.^[24]
• V$EBF1.01^[25]
  • Early B-cell factor 1 regulates B cell gene networks.^[26]
• V$IK2.01^[27]
  • Ikaros 2 is a potential regulator for lymphocyte differentiation.^[28]

Other interacting proteins

Several other proteins have been predicted to interact with C3orf67:

• CLK1^[29]
  • Phosphorylates serine/arginine-rich proteins involved in pre-mRNA processing in the nucleus.^[30]
• CDK16 (gene)^[31]
  • A protein kinase thought to play a role in signal transduction cascades in differentiated cells, exocytosis, and transport of secretory cargo from the ER.^[32]
• MARS2^[33]
  • Mitochondrial methionyl-tRNA synthetase.^[34]
• AARS2
  • mitochondrial alanyl-tRNA synthetase.
• C12orf60^[35]

Notes and References

1. Web site: NCBI Gene. National Center for Biotechnology Information.
2. Web site: C3orf67. GeneCards Human Gene Database.
3. NCBI Nucleotide. National Center for Biotechnology Information. May 2019.
4. Web site: NCBI Protein. National Center for Biotechnology Information.
5. Web site: Protein Molecular Weight Calculator. www.sciencegateway.org. 2018-02-25.
6. Web site: MOTIF: Searching Protein Sequence Motifs. www.genome.jp. 2018-02-25.
7. Web site: DictyOGlyc 1.1 Server. www.cbs.dtu.dk. en. 2018-04-30.
8. Web site: GPS-SUMO: Prediction of SUMOylation Sites & SUMO-interaction Motifs. sumosp.biocuckoo.org. 2018-04-30. 2019-02-17. https://web.archive.org/web/20190217125200/http://sumosp.biocuckoo.org/online.php. dead.
9. Web site: ExPASy - Sulfinator tool. web.expasy.org. en-US. 2018-04-30.
10. Web site: SUMOplot™ Analysis Program Abgent. www.abgent.com. en. 2018-04-30.
11. Web site: C3orf67 (human). www.phosphosite.org. 2018-04-30.
12. Web site: NetOGlyc 4.0 Server. www.cbs.dtu.dk. en. 2018-04-30.
13. Web site: YinOYang 1.2 Server. www.cbs.dtu.dk. en. 2018-04-30.
14. Web site: NetPhos 3.1 Server. www.cbs.dtu.dk. en. 2018-04-30.
15. Web site: JPred: A Protein Secondary Structure Prediction Server. www.compbio.dundee.ac.uk. en. 2018-04-24.
16. Web site: PHYRE2 Protein Fold Recognition Server. Kelley. Lawrence. www.sbg.bio.ic.ac.uk. 2018-04-24.
17. Web site: SWISS-MODEL Workspace. swissmodel.expasy.org. en. 2018-04-24.
18. Web site: Human BLAT Search. genome.ucsc.edu. 2018-04-24.
19. Web site: RNA Folding Form mfold.rit.albany.edu. unafold.rna.albany.edu. en. 2018-05-02.
20. Dezso Z, Nikolsky Y, Sviridov E, Shi W, Serebriyskaya T, Dosymbekov D, Bugrim A, Rakhmatulin E, Brennan RJ, Guryanov A, Li K, Blake J, Samaha RR, Nikolskaya T . A comprehensive functional analysis of tissue specificity of human gene expression . BMC Biology . 6 . 49 . November 2008 . 19014478 . 2645369 . 10.1186/1741-7007-6-49 . free .
21. Sato T, Kaneda A, Tsuji S, Isagawa T, Yamamoto S, Fujita T, Yamanaka R, Tanaka Y, Nukiwa T, Marquez VE, Ishikawa Y, Ichinose M, Aburatani H . PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer . En . Scientific Reports . 3 . 1 . 1911 . 2013-05-29 . 23714854 . 3665955 . 10.1038/srep01911 . 2013NatSR...3E1911S .
22. Glover KP, Chen Z, Markell LK, Han X . Synergistic Gene Expression Signature Observed in TK6 Cells upon Co-Exposure to UVC-Irradiation and Protein Kinase C-Activating Tumor Promoters . PLOS ONE . 10 . 10 . e0139850 . 2 October 2015 . 26431317 . 4592187 . 10.1371/journal.pone.0139850 . 2015PLoSO..1039850G . free .
23. Web site: Genomatix: Matrix Library information. www.genomatix.de. en-US. 2018-04-24.
24. Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B, Kern SE . Human Smad3 and Smad4 are sequence-specific transcription activators . Molecular Cell . 1 . 4 . 611–7 . March 1998 . 9660945 . 10.1016/S1097-2765(00)80061-1 . free .
25. Web site: Genomatix: Matrix Library information. www.genomatix.de. en-US. 2018-04-24.
26. Treiber T, Mandel EM, Pott S, Györy I, Firner S, Liu ET, Grosschedl R . Early B cell factor 1 regulates B cell gene networks by activation, repression, and transcription- independent poising of chromatin . Immunity . 32 . 5 . 714–25 . May 2010 . 20451411 . 10.1016/j.immuni.2010.04.013 . free .
27. Web site: Genomatix: Matrix Library information. www.genomatix.de. en-US. 2018-04-24.
28. Molnár A, Georgopoulos K . The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins . Molecular and Cellular Biology . 14 . 12 . 8292–303 . December 1994 . 7969165 . 359368 . 10.1128/MCB.14.12.8292 .
29. Lipp JJ, Marvin MC, Shokat KM, Guthrie C . SR protein kinases promote splicing of nonconsensus introns . En . Nature Structural & Molecular Biology . 22 . 8 . 611–7 . August 2015 . 26167880 . 10.1038/nsmb.3057 . 24363149 .
30. Web site: Antibodypedia - CLK1 antibodies. www.antibodypedia.com. 2018-05-01.
31. Mikolcevic P, Sigl R, Rauch V, Hess MW, Pfaller K, Barisic M, Pelliniemi LJ, Boesl M, Geley S . Cyclin-dependent kinase 16/PCTAIRE kinase 1 is activated by cyclin Y and is essential for spermatogenesis . Molecular and Cellular Biology . 32 . 4 . 868–79 . February 2012 . 22184064 . 3272973 . 10.1128/MCB.06261-11 .
32. Web site: Antibodypedia - CDK16 antibodies. www.antibodypedia.com. 2018-05-01.
33. van Meel E, Wegner DJ, Cliften P, Willing MC, White FV, Kornfeld S, Cole FS . Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype . BMC Medical Genetics . 14 . 106 . October 2013 . 24103465 . 3852179 . 10.1186/1471-2350-14-106 . free .
34. Web site: STRING: functional protein association networks. string-db.org. en. 2018-05-01.
35. Cornen S, Guille A, Adélaïde J, Addou-Klouche L, Finetti P, Saade MR, Manai M, Carbuccia N, Bekhouche I, Letessier A, Raynaud S, Charafe-Jauffret E, Jacquemier J, Spicuglia S, de The H, Viens P, Bertucci F, Birnbaum D, Chaffanet M . Candidate luminal B breast cancer genes identified by genome, gene expression and DNA methylation profiling . PLOS ONE . 9 . 1 . e81843 . 2014-01-09 . 24416132 . 3886975 . 10.1371/journal.pone.0081843 . 2014PLoSO...981843C . free .