Biology:C6orf222

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


C6orf222 is a protein that in humans is encoded by the C6orf222 gene (6p21.31).[1][2] C6orf222 is conserved in mammals, birds and reptiles with the most distant ortholog being the green sea turtle, Chelonia mydas. The C6orf222 protein contains one mammalian conserved domain: DUF3293. The protein is also predicted to contain a BH3 domain, which has predicted conservation in distant orthologs from the clade Aves.[3][4]

Gene

C6orf222 is located on the negative DNA strand of the short arm of chromosome 6 at locus 21.31. The gene is 21,129 base pairs long and extends from base pair 36315757 to 36336977. The gene produces a single transcript that is 3,750 base pairs long.[5] There is a unique upstream, in-frame stop codon in the 5’UTR region from base pairs 86-88 of the mRNA.[6]

Gene neighborhood

The gene PNPLA1 is found on the positive strand just upstream of C6orf222 and belongs to the patatin-like phospholipase family. PNPLA1 extends from base pairs 36239766 to 36313955.[7] ETV7 is found downstream on the negative strand and extends from base pairs 36354221 to 36387800.[8] There are two genes located upstream (LOC105375036) and downstream (LOC105375037) of C6orf222 on the negative and positive strand, respectively. These genes code for Non-coding RNA.[9][10]

Gene expression

There are several lines of evidence that suggest the C6orf222 protein is expressed non-ubiquitously in select tissue locations at low levels, including the ascites, bladder, intestine, testes, vagina, lymph nodes and skin. The ascites and bladder displayed the strongest expression with 25 and 66 transcripts per million, respectively.[11][12]

Promoter

The promoter region for C6orf222 is predicted to exist between 36304561 and 36305162 and has a length of 602 base pairs.[13]

Protein

C6orf222 consists of 652 amino acids, has a weight of 71.9 kDa and an isoelectric point of 8.70 in humans.[1][14][15]

Function

While the exact function of C6orf222 remains unknown, there has been evidence for it being involved in apoptosis as a pro-apoptotic protein due to the conserved BH3 interacting domain death agonist located at the C-terminus of the protein between amino acid residues 535 to 611 in humans.[3][4]

Structure

C6orf222 contains a single domain of unknown function, DUF3292, found between amino acid residues 38-110. The protein is proline rich but asparagine and tyrosine poor. The charge distribution of the protein is fairly equal in that there are no positive or negative charge clusters sequestered within the protein.[14]

A schematic representation of the conserved domains, nuclear localization signal, and phosphorylated amino acid residues in human C6orf222. The red diamond markers indicate conserved phosphoserine residues and they grey diamond markers indicate conserved phosphothreonine residues.[16]

The secondary structures of the protein were predicted via multiple bioinformatics servers. All four programs predicted extensive disorder in the protein at the N-terminus, ranging from 79% to 88% of the protein. This extent of disorder is consistent with the amino acid composition of the protein and being proline rich. There were several α-helix structures predicted at the C-terminus of the protein and conserved in orthologs of the human protein.[14][17][18][19] The protein was predominantly soluble, with a majority of the amino acid residues being exposed.15 The average of hydrophobicity for c6orf222 was -0.968, indicating the soluble nature of the protein.[20][21]

Post-translational modifications

There is extensive, predicted phosphorylation of C6orf222, with 42 phosphoserines and 7 phosphothreonines being conserved in orthologs of the human C6orf222 protein. These results implicate C6orf222 as being a phosphoprotein. The protein contains only one nuclear export signal residue, found at 275-L; however, the NES score was rather low at 0.672. Structural analysis of the protein to be sequestered in the nucleus with a 95% probability.[22] This prediction is supported by the presence of a nuclear localization sequence (NLS) found between residues 142–151.[21][23]

Protein interactions

Although the bioinformatics programs MINT, STRING and Gene Cards did not reveal any protein interactions with C6orf222.[24][25][26] A predicted BH3 domain in the C6orf222 protein was found to interact with both Bcl-2 and Bcl-xL, implicating C6orf222 as being involved in apoptosis.[4]

Table of Potential Transcription Factor Binding Sites in the Predicted C6orf222 Promoter:[13]

Transcription Factor Start End Strand Matrix Score Sequence
Myeloid zinc finger protein MZF1 115 125 - 1.000 gtGGGGaggga
Heat shock factor 2 91 115 - 0.953 aggtacctagaaAGAAaggtcagcg
NF-κβ 106 120 - 0.894 gaGGGAggtacctag
GATA-binding factor 2 133 145 + 0.958 caaaGATAactga
Pleomorphic adenoma gene 1 168 190 - 1.000 taGGGGgagaaagtcgaggtggc
TF-yin yang 2 196 218 + 0.839 catttcCCATtaagtcttgtttt
RBPJ-κ 196 208 - 0.951 ttaaTGGGaaatg
Human acute myelogenous leukemia factors 281 295 - 0.834 actGGGGtttgggt
Smad3 TF involved in TGF-β signaling 244 254 - 0.995 aagGTCTggct

Homology and evolution

Orthologous space

82 organisms have predicted orthologs with C6orf222.[2] The most distant ortholog is the green sea turtle, which diverged from humans 296 million years ago, indicating C6orf222 developed in reptiles and birds.[3][27]

Table of C6orf222 Orthologs:[3]

Scientific Name Common Name Divergence Date from Humans (MYA) [28] NCBI Protein Accession Protein Length (amino acids) Sequence Similarity (%)
Homo sapiens Human 0 NP_001010903.3 652 100
Gorilla gorilla Gorilla 8.8 XP_004043942.1 652 97
Callithrix jacchus Common marmoset 42.6 XP_002746521.2 678 81
Camelus ferus Bactrian camel 94.2 XP_006195372 658 62
Physeter catodon Sperm whale 94.2 XP_007115001.1 638 60
Orcinus orca Orca 94.2 XP_004267852.1 639 60
Canis lupus familiaris Dog 94.2 XP_850456 662 58
Mustela putorius furo Ferret 94.2 XP_004770808 664 57
Oryctolagus cuniculus Rabbit 92.3 XP_008261475 716 49
Mus musculus Mouse 92.3 NP_766038.1 669 47
Haliaeetus leucocephalus Bald eagle 296 XP_010583084.0 407 28
Fulmarus glacialis Northern fulmar 296 XP_009570924.1 435 28
Chelonia mydas Green sea turtle 296 XP_007063595.1 387 33

Paralogous space

C6orf222 rate of evolution in comparison with the fast evolving FAG gene and the slow evolving CYCS gene.

There are no predicted paralogs for C6orf222 in both humans and mice.[3]

Conserved regions

Multiple sequence alignments demonstrated amino acid reside conservation throughout the C6orf222 protein in a variety of orthologs, with the most extensive conservation being found at the C-terminus of the protein. The BH3 interacting-domain death agonist (BID) was found to be conserved at the C-terminus in a multiple sequence alignment in both strict and distant orthologs.[27] The equal distribution of positively and negatively charged amino acid residues is found to be conserved throughout orthologs of the human C6orf222 protein.[22]

Evolution

C6orf222 is a fast evolving gene, similar in nature to Fibrinogen alpha chain FGA. This evolutionary trend is in contrast to Cytochrome c, which has been shown to be a slow evolving gene.[28]

References

  1. ↑ 1.0 1.1 NCBI Protein. "uncharacterized protein c6orf222". NCBI. https://www.ncbi.nlm.nih.gov/protein/NP_001010903.3. Retrieved 23 January 2015. 
  2. ↑ 2.0 2.1 NCBI Gene. "C6orf222 chromosome 6 open reading frame 222 [ Homo sapiens (human) "]. NCBI. https://www.ncbi.nlm.nih.gov/gene?LinkName=protein_gene&from_uid=285002257. Retrieved 23 January 2015. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 NCBI BLAST. "NP_001010903:uncharacterized protein C6orf222". NCBI. http://blast.ncbi.nlm.nih.gov/Blast.cgi. Retrieved 30 January 2015. 
  4. ↑ 4.0 4.1 4.2 DeBartolo, Joe; Taipale, Mikko; Keating, Amy (June 26, 2014). "Genome-Wide Prediction and Validation of Peptides That Bind Human Prosurvival Bcl-2 Proteins". PLOS Computational Biology 10 (6): e1003693. doi:10.1371/journal.pcbi.1003693. PMID 24967846. Bibcode: 2014PLSCB..10E3693D. 
  5. ↑ Ensembl. "Gene: C6orf222". Ensembl. http://useast.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000189325;r=6:36315757-36336885;t=ENST00000437635. Retrieved 10 February 2015. 
  6. ↑ NCBI Nucleotide. "Homo sapiens chromosome 6 open reading frame 222 (C6orf222), mRNA". NCBI. https://www.ncbi.nlm.nih.gov/nuccore/NM_001010903.4. Retrieved 23 January 2015. 
  7. ↑ NCBI Gene. "PNPLA1 patatin-like phospholipase domain containing 1 [ Homo sapiens (human) "]. NCBI. https://www.ncbi.nlm.nih.gov/gene/285848. Retrieved 30 April 2015. 
  8. ↑ NCBI Gene. "ETV7 ets variant 7 [ Homo sapiens (human)"]. NCBI. https://www.ncbi.nlm.nih.gov/gene/51513. Retrieved 30 April 2015. 
  9. ↑ NCBI Gene. "LOC105375036 uncharacterized LOC105375036 [ Homo sapiens (human) "]. NCBI. https://www.ncbi.nlm.nih.gov/gene/105375036. Retrieved 30 April 2015. 
  10. ↑ NCBI Gene. "LOC105375037 uncharacterized LOC105375037 [ Homo sapiens (human) "]. NCBI. https://www.ncbi.nlm.nih.gov/gene/105375037. Retrieved 30 April 2015. 
  11. ↑ NCBI UniGene. "EST Profile: C6orf222". NCBI. https://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Hs.162104. Retrieved 25 February 2015. 
  12. ↑ The Human Protein Atlas. "C6orf222". http://www.proteinatlas.org/ENSG00000189325-C6orf222/tissue. Retrieved 28 April 2015. 
  13. ↑ 13.0 13.1 El Dorado. "Annotation and Analysis: C6orf222". Genomatix. https://www.genomatix.de/cgi-bin//eldorado/eldorado.pl?s=d1e63d8725cfd65adae7cab5ad3d9524;SHOW_ANNOTATION=c6orf222promoter_2;ELDORADO_VERSION=E28R1306. Retrieved 15 March 2015. 
  14. ↑ 14.0 14.1 14.2 Subramaniam, Shankar. "SAPS". SDSC. http://workbench.sdsc.edu/CGI/BW.cgi#!. Retrieved 11 February 2015. [yes|permanent dead link|dead link}}]
  15. ↑ ExPASy. "Compute pI/MW". ExPASy. http://web.expasy.org/cgi-bin/compute_pi/pi_tool. Retrieved 12 March 2015. [yes|permanent dead link|dead link}}]
  16. ↑ "My Domains - Image Creator". Prosite. 9 May 2015. http://prosite.expasy.org/cgi-bin/prosite/PSImage.cgi?hit=38,110,1_1,DUF3292+535,611,1_3,BH3+142,151,1_4,NLS&site=18,1+31,1+59,1+61,1+65,1+92,1+155,1+226,1+286,1+292,1+297,1+306,1+318,1+340,1+357,1+374,1+387,1+432,1+438,1+450,1+463,1+473,1+485,1+488,1+515,1+562,1+589,1+77,0+95,0+449,0&len=652&hscale=0.8. Retrieved 9 May 2015. 
  17. ↑ Kelley, Lawrence; Sternberg, Michael. "Phyre2". Structural Bioinformatics Group. http://www.sbg.bio.ic.ac.uk/phyre2/html/page.cgi?id=index. Retrieved 12 April 2015. 
  18. ↑ Källberg, Morten; Wang, Haipeng; Wang, Sheng; Peng, Jian; Wang, Zhiyong; Lu, Hui; Xu, Jinbo (2012). "Template-based protein structure modeling using the RaptorX web server". Nature Protocols 7 (8): 1511–1522. doi:10.1038/nprot.2012.085. PMID 22814390. PMC 4730388. http://raptorx.uchicago.edu/about/. Retrieved 13 April 2015. 
  19. ↑ Rost, B; Yachdav, G; Liu, J (2004). "The PredictProtein Server". Nucleic Acids Research 32 (Web Server issue): 321–326. doi:10.1093/nar/gkh377. PMID 15215403. PMC 441515. http://ppopen.informatik.tu-muenchen.de/visual_results?req_id=$1$f6HnqoJD$nvZect6knFphD0uoZdJlq1. Retrieved 12 April 2015. 
  20. ↑ Gomi, M; Sonoyama, M; Mitaku, S (2004). "High performance system for signal peptide prediction: SOSUIsignal". Chem-Bio Informatics Journal 4 (4): 142–147. doi:10.1273/cbij.4.142. http://harrier.nagahama-i-bio.ac.jp/sosui/sosuisignal/sosuisignal.cgi. Retrieved 12 April 2015. 
  21. ↑ 21.0 21.1 Kosugi, S; Hasebe, M; Matsumura, N; Takashima, H; Miyamoto-Simo, E; Tomita, M; Yanagawa, H (2009). "Six classes of nuclear localization signals specific to different binding grooves of importin α.". Journal of Biological Chemistry 284 (1): 478–485. doi:10.1074/jbc.M807017200. PMID 19001369. 
  22. ↑ 22.0 22.1 Nakai, Kenta; Horton, Paul. "PSORTII". http://psort.hgc.jp/cgi-bin/runpsort.pl. Retrieved 2 April 2015. [yes|permanent dead link|dead link}}]
  23. ↑ cNLS Mapper. "cNLS Mapper Result". http://nls-mapper.iab.keio.ac.jp/cgi-bin/NLS_Mapper_y.cgi. Retrieved 29 April 2015. 
  24. ↑ Gene Cards. "Chromosome 6 Open Reading Frame 222". Gene Cards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=C6orf222&search=8344456422fcde9038a3e5859fdd0797. Retrieved 10 February 2015. 
  25. ↑ Licata, L.; Briganti, L.; Peluso, D.; Perfetto, L.; Iannuccelli, M.; Galeota, E.; Sacco, F.; Palma, A. et al. (16 November 2011). "MINT, the molecular interaction database: 2012 update". Nucleic Acids Research 40 (D1): D857–D861. doi:10.1093/nar/gkr930. PMID 22096227. 
  26. ↑ Szklarczyk, D.; Franceschini, A.; Wyder, S.; Forslund, K.; Heller, D.; Huerta-Cepas, J.; Simonovic, M.; Roth, A. et al. (28 October 2014). "STRING v10: protein-protein interaction networks, integrated over the tree of life". Nucleic Acids Research 43 (D1): D447–D452. doi:10.1093/nar/gku1003. PMID 25352553. 
  27. ↑ 27.0 27.1 Subramaniam, Shankar. "CLUSTALW". SDSC. http://workbench.sdsc.edu/CGI/BW.cgi#!. Retrieved 1 May 2015. [yes|permanent dead link|dead link}}]
  28. ↑ 28.0 28.1 Kumar, S; Hedges, S; Dudley, J (2006). "TimeTree: a public knowledge-base of divergence times among organisms.". Bioinformatics 22 (23): 2971–2972. doi:10.1093/bioinformatics/btl505. PMID 17021158. http://www.timetree.org/. Retrieved 1 May 2015. 



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