C1orf185 Explained

Chromosome 1 open reading frame 185, also known as C1orf185, is a protein that in humans is encoded by the C1orf185 gene. In humans, C1orf185 is a lowly expressed protein that has been found to be occasionally expressed in the circulatory system.^{[1] [2]}

Gene

C1orf185 is located on chromosome 1 in humans on the positive strand between bases 51,102,221 and 51,148,086.^[3] There are 5 exons in the main splice isoform, however the number and selection of exons varies based on the isoform

mRNA and Protein Isoforms

C1orf185 has 5 different splice isoforms in humans.

C1orf185 Transcripts!Isoform!mRNA Accession!Protein Accession!Transcript Length (bp)!Protein Length (AA)

uncharacterized protein C1orf185	NM_001136508.2	NP_001129980.1	921	199
uncharacterized protein C1orf185 isoform X1	XM_011541282.2	XP_011539584.1	787	195
uncharacterized protein C1orf185 isoform X2	XM_024446525.1	XP_024302293.1	586	116
uncharacterized protein C1orf185 isoform X3	XM_024446528.1	XP_024302296.1	420	116
uncharacterized protein C1orf185 isoform X4	XM_024446529.1	XP_024302297.1	367	107

Protein

C1orf185 is a member of the pfam15842 protein family, containing a domain of unknown function, DUF4718.^[4] This family of proteins is between 130 and 224 amino acids long, and is found only in eukaryotes..

The main splice isoform of C1orf185 has a molecular weight of 22.4 kDa^[5] and an isoelectric point of 7.67.^[6] It contains a transmembrane domain spanning from positions 15 to 37. There is also a conserved serine-rich region from S123 to S142, which could possibly indicate function as a "splicing activator".^[7]

C1orf185 contains 3 primary subcellular domains: an extracellular domain which spans the amino acids from positions 1 to 14, a transmembrane domain from positions 15–37, and a large intracellular domain from positions 38–199.^[8]

Below are predicted secondary and tertiary structures of C1orf185, modeled using the Chou-Fasman^[9] secondary structure prediction tool and the I-TASSER^[10] protein structure and function prediction tool. Chou-Fasman predicts a mixture of α-helices, β-sheets, and other structural turns and coils, which can be seen modeled on the I-TASSER prediction.

Regulation of Expression

Gene Level Regulation

Below is a diagram showing the locations of predicted transcription factor binding sites in the C1orf185 promoter, along with a table describing the attributes of each individual binding site. The transcription factors were found and analyzed using the ElDorado tool from Genomatix.^[11]

Transcription Factor

Detailed matrix info	Matrix similarity	Sequence	+/-
VTATA.02	Mammalian C-type LTR TATA box	0.91	tgtcaTAAAaacattcc	+|-|NKX25.05|Homeodomain factor Nkx-2.5/Csx|0.986|tttttTGAGtgaagtcttg|-
CDX1.01	Intestine specific homeodomain factor CDX-1	0.988	ttgccctTTTAtgaaaaaa	+|-|VTATA.02|Mammalian C-type LTR TATA box|0.914|tacttTAAAaataagca|-|-|ERG.02|v-ets erythroblastosis virus E26 oncogene homolog|0.942|gtctcaaaGGAAaataaaaag|-|-|SPI1.02|SPI-1 proto-oncogene; hematopoietic transcription factor PU.1|0.992|attaaagaGGAAgtctcaaag|-
FHXB.01	Fork head homologous X binds DNA with a dual sequence specificity (FHXA and FHXB)	0.831	ttctaaATAAcacattt	-|-|TGIF.01|TG-interacting factor belonging to TALE class of homeodomain factors|1|tctataaatGTCAatta|+|-|ZNF219.01|Kruppel-like zinc finger protein 219|0.913|ctccaCCCCcgtcagcccaaagg|+|-|ZBP89.01|Zinc finger transcription factor ZBP-89|0.956|catctccaCCCCcgtcagcccaa|+|-|CREB.02|cAMP-responsive element binding protein|0.922|cctttgggcTGACgggggtgg|-
FOXP1_ES.01	Alternative splicing variant of FOXP1, activated in ESCs	1	tcataaaAACAttccag	-|-|VTATA.02|Mammalian C-type LTR TATA box|0.895|tgtcaTAAAaacattcc|-|-|CREB1.02|cAMP-responsive element binding protein 1|0.949|tggaaGTGAtgtcataaaaac|-|-|SPI1.02|SPI-1 proto-oncogene; hematopoietic transcription factor PU.1|0.979|atttgagtGGAAgtgatgtca|-
NKX25.05	Homeodomain factor Nkx-2.5/Csx	0.994	gaattTGAGtggaagtgat	-|-|MESP1_2.01|Mesoderm posterior 1 and 2|0.917|cagtCATAtggct|+
MESP1_2.01	Mesoderm posterior 1 and 2	0.929	aagcCATAtgact	-|-|DELTAEF1.01|deltaEF1|0.99|gcttcACCTaaag|+
ERG.02	v-ets erythroblastosis virus E26 oncogene homolog	0.93	gaagaagaGGAAaatatattt	+|}Matrix similarity correlates to the confidence in the prediction for each individual binding sites. +/- correlates to presence on either the positive or negative strand. The transcription factors are listed in order of appearance from beginning to end of the promoter. C1orf185 has a very low expression pattern, with the only site in the body showing any signs of expression being the circulatory system. Two NCBI GEO profiles have shown that C1orf185 was consistently overexpressed in whole blood samples within a group of postmenopausal women,^[12] as well as being somewhat overexpressed in the peripheral blood of Parkinson's patients compared to controls.^[13] Transcript Level Regulation Below is a figure produced by ^[14] showing predicted mRNA structure of the 3' UTR of C1orf185. C1orf185 has one conserved miRNA binding site of type 7mer-A1 among several orthologs.^[15] The presence of a 7mer-A1 binding site indicates that C1orf185 is likely to be post-transcriptionally repressed.^[16] Protein Level Regulation Below is a figure and table showing predicted post-translational modification sites for C1orf185. Table of Post-Translational Modifications for C1orf185!Type of Modification!Tool!Positions in Homo sapiens Phosphorylation NetPhos^[17] S61, S69, S104, S130, S142, S147, S165, S186 Glycation NetGlycate,^[18] NetNGlyc^[19] K5, K50, K98, K113 O-GlcNAc YinOYang^[20] T121, S122, S130 The presence of multiple leucine glycation sites indicate that there may be ways to deter the function of the protein, as glycation has been associated with the loss of protein function in blood vessels^[21] Clinical Significance C1orf185 has been shown to play a role in the circulatory system, likely in a more reactive role, as it is lowly expressed across many species. It appears in studies surrounding atrial fibrillation and abnormal QRS duration, which implies it may play a role in those circulatory diseases. Homology Below is a table showing C1orf185 orthologs across a variety of conserved species. Orthologs were found using NCBI BLAST,^[22] the dates of divergence were found using TimeTree,^[23] and the global sequence identities and similarities were found using the Clustal Omega multiple sequence alignment tool.^[24] Ortholog Table for C1orf185.!Genus and Species!Common Name!Taxonomic Group!Date of Divergence (MYA)!Accession Number!Sequence Length (aa)!Sequence Identity (Global)!Sequence Similarity (Global) Homo sapiens Human Primates 0 NP_001129980.1 199 100% 100% Pongo abelii Sumatran orangutan Primates 15.76 PNJ53823.1 195 93.50% 95.50% Cebus capucinus imitator Capuchin Primates 43.2 XP_017404303.1 229 77.00% 79.60% Galeopterus variegatus Sunda flying lemur Dermoptera 76 XP_008578352.1 203 73.70% 77.90% Oryctolagus cuniculus Rabbit Lagomorpha 90 XP_008263491.1 225 69.90% 76.40% Dipodomys ordii Ord's kangaroo rat Rodentia 90 XP_012877642.1 188 52.20% 59.40% Mastomys coucha Southern multimammate mouse Rodentia 90 XP_031234037 263 51.50% 61.50% Mus musculus House mouse Rodentia 90 NP_001186019.1 226 47.40% 59.50% Peromyscus leucopus White-footed mouse Rodentia 90 XP_028745885.1 295 41% 48.20% Phyllostomus discolor Pale spear-nosed bat Chiroptera 96 XP_028367083.1 191 73.40% 80.40% Myotis davidii David's myotis Chiroptera 96 XP_006768446.1 196 71.40% 78.40% Equus caballus Horse Perissodactyla 96 XP_023485921.1 243 63.80% 68.30% Muntiacus muntjak Indian muntjac Artiodactyla 96 KAB0362285.1 200 59.40% 65.90% Hipposideros armiger Great roundleaf bat Chiroptera 96 XP_019487867.1 157 54.90% 59.20% Tursiops truncatus Bottlenose dolphin Artiodactyla 96 XP_033708766.1 189 54.10% 59.00% Sarcophilus harrisii Tasmanian devil Dasyuromorhpia 159 XP_031825005.1 333 18.20% 27.70% Ornithorhynchus anatinus Platypus Monotremata 180 XP_028902271 309 26.80% 37.40% Pelodiscus sinensis Chinese softshell turtle Reptilia 312 XP_025042106.1 890 7.40% 11.40% Gopherus evgoodei Sinaloan thornscrub tortoise Reptilia 312 XP_030429802.1 777 4.00% 6.30% Chrysemys picta bellii Western painted turtle Reptilia 312 XP_023960730.1 748 3.70% 5.80% Compared to other genes, C1orf185 appears to be evolving and changing relatively quickly, as it is only conserved in mammals and a few turtles, and more distant mammals have quite distant similarities. Primates are the only taxonomic group that heavily conserves this gene with regards to the human sequence, while other mammals and turtles only heavily conserve the transmembrane domain (positions 15–37). As primates and mammals are warm-blooded, this may further support the evidence showing a possible role in the circulatory system. References ]

Notes and References

1. Sotoodehnia N, Isaacs A, de Bakker PI, Dörr M, Newton-Cheh C, Nolte IM, van der Harst P, Müller M, Eijgelsheim M, Alonso A, Hicks AA, Padmanabhan S, Hayward C, Smith AV, Polasek O, Giovannone S, Fu J, Magnani JW, Marciante KD, Pfeufer A, Gharib SA, Teumer A, Li M, Bis JC, Rivadeneira F, Aspelund T, Köttgen A, Johnson T, Rice K, Sie MP, Wang YA, Klopp N, Fuchsberger C, Wild SH, Mateo Leach I, Estrada K, Völker U, Wright AF, Asselbergs FW, Qu J, Chakravarti A, Sinner MF, Kors JA, Petersmann A, Harris TB, Soliman EZ, Munroe PB, Psaty BM, Oostra BA, Cupples LA, Perz S, de Boer RA, Uitterlinden AG, Völzke H, Spector TD, Liu FY, Boerwinkle E, Dominiczak AF, Rotter JI, van Herpen G, Levy D, Wichmann HE, van Gilst WH, Witteman JC, Kroemer HK, Kao WH, Heckbert SR, Meitinger T, Hofman A, Campbell H, Folsom AR, van Veldhuisen DJ, Schwienbacher C, O'Donnell CJ, Volpato CB, Caulfield MJ, Connell JM, Launer L, Lu X, Franke L, Fehrmann RS, te Meerman G, Groen HJ, Weersma RK, van den Berg LH, Wijmenga C, Ophoff RA, Navis G, Rudan I, Snieder H, Wilson JF, Pramstaller PP, Siscovick DS, Wang TJ, Gudnason V, van Duijn CM, Felix SB, Fishman GI, Jamshidi Y, Stricker BH, Samani NJ, Kääb S, Arking DE . 6 . Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction . Nature Genetics . 42 . 12 . 1068–76 . December 2010 . 21076409 . 3338195 . 10.1038/ng.716 .
2. Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM, Almgren P, Alonso A, Anderson CD, Aragam KG, Arking DE, Barnard J, Bartz TM, Benjamin EJ, Bihlmeyer NA, Bis JC, Bloom HL, Boerwinkle E, Bottinger EB, Brody JA, Calkins H, Campbell A, Cappola TP, Carlquist J, Chasman DI, Chen LY, Chen YI, Choi EK, Choi SH, Christophersen IE, Chung MK, Cole JW, Conen D, Cook J, Crijns HJ, Cutler MJ, Damrauer SM, Daniels BR, Darbar D, Delgado G, Denny JC, Dichgans M, Dörr M, Dudink EA, Dudley SC, Esa N, Esko T, Eskola M, Fatkin D, Felix SB, Ford I, Franco OH, Geelhoed B, Grewal RP, Gudnason V, Guo X, Gupta N, Gustafsson S, Gutmann R, Hamsten A, Harris TB, Hayward C, Heckbert SR, Hernesniemi J, Hocking LJ, Hofman A, Horimoto AR, Huang J, Huang PL, Huffman J, Ingelsson E, Ipek EG, Ito K, Jimenez-Conde J, Johnson R, Jukema JW, Kääb S, Kähönen M, Kamatani Y, Kane JP, Kastrati A, Kathiresan S, Katschnig-Winter P, Kavousi M, Kessler T, Kietselaer BL, Kirchhof P, Kleber ME, Knight S, Krieger JE, Kubo M, Launer LJ, Laurikka J, Lehtimäki T, Leineweber K, Lemaitre RN, Li M, Lim HE, Lin HJ, Lin H, Lind L, Lindgren CM, Lokki ML, London B, Loos RJ, Low SK, Lu Y, Lyytikäinen LP, Macfarlane PW, Magnusson PK, Mahajan A, Malik R, Mansur AJ, Marcus GM, Margolin L, Margulies KB, März W, McManus DD, Melander O, Mohanty S, Montgomery JA, Morley MP, Morris AP, Müller-Nurasyid M, Natale A, Nazarian S, Neumann B, Newton-Cheh C, Niemeijer MN, Nikus K, Nilsson P, Noordam R, Oellers H, Olesen MS, Orho-Melander M, Padmanabhan S, Pak HN, Paré G, Pedersen NL, Pera J, Pereira A, Porteous D, Psaty BM, Pulit SL, Pullinger CR, Rader DJ, Refsgaard L, Ribasés M, Ridker PM, Rienstra M, Risch L, Roden DM, Rosand J, Rosenberg MA, Rost N, Rotter JI, Saba S, Sandhu RK, Schnabel RB, Schramm K, Schunkert H, Schurman C, Scott SA, Seppälä I, Shaffer C, Shah S, Shalaby AA, Shim J, Shoemaker MB, Siland JE, Sinisalo J, Sinner MF, Slowik A, Smith AV, Smith BH, Smith JG, Smith JD, Smith NL, Soliman EZ, Sotoodehnia N, Stricker BH, Sun A, Sun H, Svendsen JH, Tanaka T, Tanriverdi K, Taylor KD, Teder-Laving M, Teumer A, Thériault S, Trompet S, Tucker NR, Tveit A, Uitterlinden AG, Van Der Harst P, Van Gelder IC, Van Wagoner DR, Verweij N, Vlachopoulou E, Völker U, Wang B, Weeke PE, Weijs B, Weiss R, Weiss S, Wells QS, Wiggins KL, Wong JA, Woo D, Worrall BB, Yang PS, Yao J, Yoneda ZT, Zeller T, Zeng L, Lubitz SA, Lunetta KL, Ellinor PT . 6 . Multi-ethnic genome-wide association study for atrial fibrillation . Nature Genetics . 50 . 9 . 1225–1233 . June 2018 . 29892015 . 10.1038/s41588-018-0133-9 . 6136836 .
3. Web site: C1orf185 chromosome 1 open reading frame 185 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2020-05-01.
4. Web site: CDD Conserved Protein Domain Family: DUF4718. www.ncbi.nlm.nih.gov. 2020-05-01.
5. Web site: SAPS < Sequence Statistics < EMBL-EBI. www.ebi.ac.uk. 2020-05-01.
6. Web site: ExPASy - Compute pI/Mw tool. web.expasy.org. 2020-05-01.
7. Graveley BR, Maniatis T . Arginine/serine-rich domains of SR proteins can function as activators of pre-mRNA splicing . Molecular Cell . 1 . 5 . 765–71 . April 1998 . 9660960 . 10.1016/s1097-2765(00)80076-3 . free .
8. Web site: TMHMM Server, v. 2.0. www.cbs.dtu.dk. 2020-05-01.
9. Web site: CFSSP: Chou & Fasman Secondary Structure Prediction Server. www.biogem.org. 2020-05-01.
10. Web site: I-TASSER server for protein structure and function prediction. zhanglab.ccmb.med.umich.edu. 2020-05-01.
11. Web site: Genomatix - NGS Data Analysis & Personalized Medicine. www.genomatix.de. 2020-05-01.
12. Web site: 13889230 - GEO Profiles - NCBI. www.ncbi.nlm.nih.gov. 2020-05-01.
13. Web site: 129780050 - GEO Profiles - NCBI. www.ncbi.nlm.nih.gov. 2020-05-01.
14. Web site: The Mfold Web Server mfold.rit.albany.edu. unafold.rna.albany.edu. 2020-05-01.
15. Web site: TargetScanHuman 7.2. www.targetscan.org. 2020-05-01.
16. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP . MicroRNA targeting specificity in mammals: determinants beyond seed pairing . Molecular Cell . 27 . 1 . 91–105 . July 2007 . 17612493 . 3800283 . 10.1016/j.molcel.2007.06.017 .
17. Web site: NetPhos 3.1 Server. www.cbs.dtu.dk. 2020-05-01.
18. Web site: NetGlycate 1.0 Server. www.cbs.dtu.dk. en. 2020-05-01.
19. Web site: NetNGlyc 1.0 Server. www.cbs.dtu.dk. 2020-05-01.
20. Web site: YinOYang 1.2 Server. www.cbs.dtu.dk. 2020-05-01.
21. Kim CS, Park S, Kim J . The role of glycation in the pathogenesis of aging and its prevention through herbal products and physical exercise . Journal of Exercise Nutrition & Biochemistry . 21 . 3 . 55–61 . September 2017 . 29036767 . 5643203 . 10.20463/jenb.2017.0027 .
22. Web site: BLAST: Basic Local Alignment Search Tool. blast.ncbi.nlm.nih.gov. 2020-05-01.
23. Web site: TimeTree :: The Timescale of Life. www.timetree.org. 2020-05-01.
24. Web site: Clustal Omega < Multiple Sequence Alignment < EMBL-EBI. www.ebi.ac.uk. 2020-05-01.