Biology:C6orf136

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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

C6orf136 (Chromosome 6 Open Reading Frame 136) is a protein in humans (Homo sapiens) encoded by the C6orf136 gene. The gene is conserved in mammals, mollusks, as well some porifera.[1] While the function of the gene is currently unknown, C6orf136 has been shown to be hypermethylated in response to FOXM1 expression in Head Neck Squamous Cell Carcinoma (HNSCC) tissue cells.[2] Additionally, elevated expression of C6orf136 has been associated with improved survival rates in patients with bladder cancer.[3] C6orf136 has three known isoforms.

Gene

Background

C6orf136, also known as DADB-129D20.1, MGC15854, LOC221545, and OTTHUMP00000214979. The gene is a poorly characterized protein coding gene in need of further research. The C6orf136 gene can be accessed on NCBI with accession number NM_001109938.3.

Location

C6orf136 is located on the short arm of chromosome 6 (6p21.33), starting at base pair (bp) 30,647,133 and ending at bp 30,653,207. This gene spans 6,074 bit/s on the plus (+) strand and contains a total of 6 exons.[4]

Gene Neighborhood

Genes in the neighborhood of C6orf136 are the following: ATAT1, PPP1R10, DHX16, PPP1R18, MDC1, MRPS18B, TUBB, and FLOT1.[4]

mRNA

C6orf136 has a total of 3 different isoforms. Isoform 1 is the base version of C6orf136 that encodes for the 315 amino acid protein. Isoform 3 uses an alternate in-frame splice site in the 5' coding region when compared to isoform 1, resulting in isoform 3 being longer than isoform 1. Alternatively, isoform 2 lacks an alternate in-frame exon in the 5' coding region when compared to isoform 1, resulting an isoform 2 being shorter than isoform 1

Protein

General Properties

The sequence for the C6orf136 isoform 1 gene per NCBI is as follows:[5] 

MYQPSRGAARRLGPCLRAYQARPQDQLYPGTLPFPPLWPHSTTTTSPSSPLFWSPLPPRLPTQRLPQVPP  70
LPLPQIQALSSAWVVLPPGKGEEGPGPELHSGCLDGLRSLFEGPPCPYPGAWIPFQVPGTAHPSPATPSG 140
DPSMEEHLSVMYERLRQELPKLFLQSHDYSLYSLDVEFINEILNIRTKGRTWYILSLTLCRFLAWNYFAH 210
LRLEVLQLTRHPENWTLQARWRLVGLPVHLLFLRFYKRDKDEHYRTYDAYSTFYLNSSGLICRHRLDKLM 280
PSHSPPTPVKKLLVGALVALGLSEPEPDLNLCSKP                                    315

The bolded region in this sequence indicates a domain of unknown function (DUF2358) found in all three isoforms of C6orf136.

The C6orf136 protein has a molecular weight of 35.8 kD and an isoelectric point of 8.99, making the protein slightly basic and physiological pH.

Domains

DUF2358 is a domain of unknown function found within the C6orf136 protein from aa149 to aa274.[6] This domain is highly conserved in the C-terminus region and is evolutionarily conserved from plants to humans.[7] Additionally, a proline rich domain was also predicted from aa29 to aa142 of the human C6orf136 protein.[6]

Schematic illustration of the C6orf136 protein with proline rich domain and DU2358 domain. The gray markers indicate predicted phosphorylation sites, and the red marker indicates a predicted SUMOylation site. Image made with Prosite MyDomains tool.
Schematic illustration of the C6orf136 protein with proline rich domain and DU2358 domain. The gray markers indicate predicted phosphorylation sites, and the red marker indicates a predicted SUMOylation site. Image made with Prosite MyDomains tool.

Structure

Secondary Structure

The conserved DUF2358 domain of C6orf136 contains an equal mix of alpha helices and beta sheets interspersed in that region.[8][9][10] The N-terminus of the protein contained primarily alpha helices, but was poorly conserved across species.

Tertiary Structure

The tertiary structure illustrates a primarily alpha helices in the N-terminus of the protein loosely wound up, followed by a densely packed and folded region correlating to the DUF2358 domain with a mix of alpha helices and beta sheets as determined by I-TASSER.[11][12][13]

Regulation

Gene Regulation

Promotor

C6orf136 has 5 predicted promotor regions. The GXP_6051617 promotor had the largest number of transcripts and CAGE tags. It's located on the plus (+) strand, starts at position 30646644, ends at position 30647460, and is 817 bp in length. It also has 12 total coding transcripts.[14]

Schematic diagram of the C6orf136 mRNA transcript with the ElDorado suggested promotor sites and axons labelled. Regions are not drawn to scale.
Schematic diagram of the C6orf136 mRNA transcript with the ElDorado suggested promotor sites and axons labelled. Regions are not drawn to scale.
Promotor Regions of C6orf136
Promotor ID Start Position End Position Length # of Coding Transcripts
GXP_6051617 (+) 30646644 30647460 817 12
GXP_2563514 (+) 30648906 30649945 1040 1
GXP_6051618 (+) 30650054 30651093 1040 1
GXP_6051619 (+) 30650266 30651423 1158 2
GXP_3204858 (+) 30651611 30652650 1040 0

Transcription Factor Binding Sites

The following table highlights the most likely transcription factors binding to the GXP_6051617 promotor for C6orf136.[14]

Matrix Family Detailed Family Information
V$ZF15 C2H2 zinc finger transcription factors 15
V$NRF1 Nuclear respiratory factor 1
V$MYBL Cellular and viral myb-like transcriptional regulators
V$CALM Calmodulin-binding transcription factors
V$ZF07 C2H2 zinc finger transcription factors 7
V$ZF5F ZF5 POZ domain zinc finger
V$HAND Twist subfamily of class B bHLH transcription factors
V$KLFS Krueppel like transcription factors
V$SP1F GC-Box factors SP1/GC
V$EGRF EGR/nerve growth factor induced protein C & related factors
V$PLAG Pleomorphic adenoma gene
V$EBOX E-box binding factors
V$RXRF RXR heterodimer binding sites
V$RREB Ras-responsive element binding protein
V$NKXH NKX homeodomain factors
V$ETSF Human and murine ETS1 factors
V$CEBP Ccaat/Enhancer Binding Protein

Expression Pattern

C6orf136 is expressed highly in the heart, intestine, brain, and kidney tissue.[4] According to AceView, it is well expressed at 1.3x the average gene expression.[15]

Transcription Regulation

Stem Loop Prediction

The 3’ UTR sequence had a total of 7 step loops with a single site for potential miRNA binding. In contrast, the 5’ UTR had only 2 stem loops and contained no other notable regions.[16]

miRNA Targeting

TargetScan indicated a single has-miRNA-585-3p miRNA binding site in the 3' UTR, shown to be associated with tumor-suppressing properties with respect to gastric cancer.[17][18]

Protein Regulation

Subcellular Localization

C6orf136 is predicted to be localized primarily in the nucleus in Homo sapiens, but is predicted to be primarily expressed in the mitochondria in other species.[19]

Post-Translational Modification

The C6orf136 gene has 8 predicted kinase-specific phosphorylation sites at positions 5, 28, 137, 139, 191, 256, 261, and 303, where 4 of the phosphorylation sites are serines, 3 sites are threonines, and 1 is a tryptophan.[20] Additionally, the protein also has a single predicted SUMOylation site at position 247 on a lysine with a p-value of 0.063.[21]

Homology

Paralogs

Relative mutation rate of C6orf136 (blue) compared to fibrinogen alpha (grey) and cytochrome C (orange)

No paralogs of C6orf136 have been detected in the human genome.

Orthologs

Below is a table of selected orthologs of the C6orf136 gene, including closely and distantly related orthologs.[22] C6orf136 has evolved moderately and evenly over time with a rate faster than Cytochrome C but slower than Fibrinogen Alpha.

Selected Orthologs of C6orf136
Genus and Species Common Name Taxon Class Date of Divergence (MYA) Accession # Length (AA) % Identity with Human % Similarity with Human
Homo sapiens Humans Primates 0 NP_001103408.1 315 100% 100%
Pan troglodytes Chimpanzee Primates 6.4 PNI76372.1 315 100% 100%
Mus musculus Mouse Rodentia 89 EDL23245.1 315 80% 87%
Chiroxiphia lanceolata Lance-tailed manakin Passerine 318 XP_032533412.1 384 60% 76%
Chelonia mydas Sea Turtle Testudines 318 XP_007068287.2 386 63% 74%
Gopherus evgoodei Gopher tortoise Testudines 318 XP_030399707.1 320 60% 72%
Melopsittacus undulatus Parakeet Psittaciformes 318 XP_033929477.1 288 61% 76%
Geotrypetes seraphini Gaboon caecilian Gymnophiona 351.7 XP_033771275.1 416 56% 70%
Danio rerio Zebrafish Cypriniformes 433 NP_001076315.1 423 49% 70%
Apostichopus japonicus Sea cucumber Synallactida 627 PIK49576.1 376 41% 59%
Strongylocentrotus purpuratus Sea Urchin Echinoida 627 XP_030853574.1 518 38% 56%
Branchiostoma floridae Lancelet Lancelet 637 XP_035683876.1 460 45% 64%
Aplysia californica Sea hare Aplysiidae 736 XP_005104721.2 409 25% 50%
Anopheles darlingi Malaria mosquito Diptera 736 ETN63757.1 303 36% 53%
Crassostrea virginica Oyster Ostreoida 736 XP_022320078.1 359 27% 44%
Ixodes scapularis Ticks Ixodida 736 XP_029848376.1 352 35% 51%
Mytilus coruscus hard-shelled mussel Mytilida 736 CAC5413351.1 363 33% 59%
Pomacea canaliculata Channeled applesnail Mollusca 736 XP_025112199.1 286 24% 39%
Wasmannia auropunctata Electric ant Hymenoptera 736 XP_011701036.1 387 36% 56%
Trichoplax adhaerens Trichoplax Tricoplaciformes 747 XP_002109420.1 415 34% 57%
Amphimedon queenslandica Porifera Porifera 777 XP_019852039.1 303 33% 7%

Function

Proteins Interacting with C6orf136
Protein Function Method Databases Present in Total # of appearances
CSNK2B Localized to ER and Golgi, and involved with regulating metabolic pathways, signal transduction, transcription, translation, and replication.[23] Y2H iRefIndex; MINT; IMEx; mentha 13
PLK1 Regulates cell cycle, specifically G2/M transition. Loss of PLK1 expression can induce pro-apoptotic pathways. This is being studied as a target for cancer drugs, specifically colon and lung cancers that are dependent on PLK1. (Oncogene). Also possible leukemia involvement.[24] Y2H iRefIndex; MINT; InnateDB-ALL; IMEx; mentha 11
RBM8A Found predominantly in nucleus, but also in cytoplasm. Is associated with the mRNAs produced after splicing, and is thought to act as a tag to indicate where introns were present, thus coupling pre- and post-mRNA binding events.[25] Y2H; Affinity Chromotography; Anti-Tag Coimmunoprecipitation iRefIndex; InnateDB-All; MatrixDB; IntAct; IMEx; metha 6
KIF21A Kinesin-like protein (motor protein). Could be involved in microtubule dependent transport. Mutation of this gene results in fibrosis of extraocular muscles. Not much else is currently known about this gene.[26] Affinity Chromotography; Anti-Tag Coimmunoprecipitation MatrixDB; IntAct; IMEx; mentha 4
FBXW7 Gene that encodes for many proteins in the F-box protein family. Mutations in this gene are associated with a variety of cancers (cholangiocarcinoma, Endometrial carcinoma, colorectal carcinoma, bladder cancer, gastric carcinoma, lung squamous cell carcinoma, etc.). Thus it's likely that this gene plays a role in the pathogenesis of human cancers.[27] Genetic Interference InnateDB- 1

References

  1. ↑ "C6orf136 orthologs" (in en). https://www.ncbi.nlm.nih.gov/gene/221545/ortholog/. 
  2. ↑ "Identification of FOXM1-induced epigenetic markers for head and neck squamous cell carcinomas". Cancer 119 (24): 4249–58. December 2013. doi:10.1002/cncr.28354. PMID 24114764. 
  3. ↑ "Cancer stem cell-specific expression profiles reveal emerging bladder cancer biomarkers and identify circRNA_103809 as an important regulator in bladder cancer". Aging 12 (4): 3354–3370. February 2020. doi:10.18632/aging.102816. PMID 32065779. 
  4. ↑ 4.0 4.1 4.2 "C6orf136 chromosome 6 open reading frame 136 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/221545. 
  5. ↑ "uncharacterized protein C6orf136 isoform 1 [Homo sapiens - Protein - NCBI"]. https://www.ncbi.nlm.nih.gov/protein/NP_001103408.1. 
  6. ↑ 6.0 6.1 "Motif Scan" (in en). https://myhits.sib.swiss/cgi-bin/motif_scan. 
  7. ↑ "Pfam: Family: DUF2358 (PF10184)". http://pfam.xfam.org/family/DUF2358. 
  8. ↑ "I-TASSER server for protein structure and function prediction". https://zhanglab.ccmb.med.umich.edu/I-TASSER/. 
  9. ↑ "PHYRE2 Protein Fold Recognition Server". http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index. 
  10. ↑ "Bioinformatics Toolkit". https://toolkit.tuebingen.mpg.de/tools/ali2d. 
  11. ↑ "I-TASSER: a unified platform for automated protein structure and function prediction". Nature Protocols 5 (4): 725–38. April 2010. doi:10.1038/nprot.2010.5. PMID 20360767. 
  12. ↑ "I-TASSER server: new development for protein structure and function predictions". Nucleic Acids Research 43 (W1): W174-81. July 2015. doi:10.1093/nar/gkv342. PMID 25883148. 
  13. ↑ "The I-TASSER Suite: protein structure and function prediction". Nature Methods 12 (1): 7–8. January 2015. doi:10.1038/nmeth.3213. PMID 25549265. 
  14. ↑ 14.0 14.1 "Genomatix - NGS Data Analysis & Personalized Medicine". https://www.genomatix.de/index.html. 
  15. ↑ "AceView: Gene:C6orf136, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView.". https://www.ncbi.nlm.nih.gov/ieb/research/acembly/av.cgi?db=human&term=c6orf136&submit=Go. 
  16. ↑ "miRDB - MicroRNA Target Prediction Database". http://www.mirdb.org. 
  17. ↑ "TargetScanHuman 7.2". http://www.targetscan.org/vert_72/. 
  18. ↑ "The colorectal microRNAome". Proceedings of the National Academy of Sciences of the United States of America 103 (10): 3687–92. March 2006. doi:10.1073/pnas.0511155103. PMID 16505370. Bibcode: 2006PNAS..103.3687C. 
  19. ↑ "PSORT II Prediction". https://psort.hgc.jp/form2.html. 
  20. ↑ "GPS 5.0 - Kinase-specific Phosphorylation Site Prediction". http://gps.biocuckoo.cn/online.php. 
  21. ↑ "GPS-SUMO: Prediction of SUMOylation Sites & SUMO-interaction Motifs". http://sumosp.biocuckoo.org/online.php. 
  22. ↑ "Protein BLAST: search protein databases using a protein query". https://blast.ncbi.nlm.nih.gov/Blast.cgi?PROGRAM=blastp&PAGE_TYPE=BlastSearch&LINK_LOC=blasthome. 
  23. ↑ "CSNK2B Gene - GeneCards | CSK2B Protein | CSK2B Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=CSNK2B. 
  24. ↑ "PLK1 Gene - GeneCards | PLK1 Protein | PLK1 Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=PLK1. 
  25. ↑ "RBM8A Gene - GeneCards | RBM8A Protein | RBM8A Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=RBM8A. 
  26. ↑ "KIF21A Gene - GeneCards | KI21A Protein | KI21A Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=KIF21A. 
  27. ↑ "FBXW7 Gene - GeneCards | FBXW7 Protein | FBXW7 Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=FBXW7. 



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