Biology:C19orf67
UPF0575 protein C19orf67 is a protein which in humans (Homo sapiens) is encoded by the C19orf67 gene.[1] Orthologs of C19orf67 are found in many mammals, some reptiles, and most jawed fish.[2][3] The protein is expressed at low levels throughout the body with the exception of the testis and breast tissue.[4][5] Where it is expressed, the protein is predicted to be localized in the nucleus to carry out a function. The highly conserved and slowly evolving DUFF3314 region is predicted to form numerous alpha helices and may be vital to the function of the protein.
Gene
In humans, C19orf67 is located on the minus strand of Chromosome 19 at 19p13.12 and spans 4,163 base pairs (bp).[1][6]
The following genes are found near C19orf67 on the positive strand:[1]
- MISP3
- Eukaryotic Translation Elongation Factor 1 Delta Pseudogene 1 (EEF1DP1)
- MicroRNA 1199 (MIR1199)
The following genes are found near C19orf67 on the minus strand:[1]
mRNA transcript
C19orf67 has three transcript variants, although the second and third variants are only predicted by an Ensembl analysis and not experimentally confirmed.[7] Only the first two variants are protein-coding transcripts.
The first transcript consists of 1447bp while the second and third have 751bp and 656bp respectively.[7] The mature mRNA of the longest isoform is made up from 6 exons.
Protein
The unmodified protein has 358 amino acids, predicted molecular weight of 40kDa, charge of -11, and isoelectric point of 5.[8][9] 44 prolines were found along the protein, making up 12.3% of the total amino acid sequence. The proline content by percentage was found to be higher in UPF0575 than 95% of comparable human proteins. However, the amount of asparagine the protein is less abundant when compared to the human proteome.[9]
Domains
Both isoforms contain DUF3314. Although the function is not yet well understood, conservation among numerous taxa indicate that it may be important to the function of the protein.[2][10] The first isoform has a non-repeating proline-rich region from amino acids 12 to 80.[11] The function of the region is not well understood but it may be involved in preventing helices from forming due to the rigid structure of proline.[12]
Secondary structure
A cross-program consensus predicted that UPF0575 protein C19orf67 forms four alpha helices and two beta sheets in the following locations in the amino acid sequence:[13][14]
| Helix | 52-62 | 90-108 | 115-125 | 153-180 |
| Sheet | 193-202 | 210-217 |
Post-translational modifications
Acetylation is likely to occur at the N-terminus while the C-terminus is unlikely to be modified.[15][16] O-Glycosylation is predicted to occur at amino acids 18 and 67. Several possible phosphorylation sites were identified along with the associated kinases:[17][18] File:Post mods.tif
| Location | Amino acid | Kinase |
|---|---|---|
| 67 | Serine | cdk5 |
| 127 | Threonine | PKC |
| 169 | Threonine | PKC |
| 196 | Serine | cdc2 |
| 204 | Serine | PKA |
| 299 | Tyrosine | SRC |
| 346 | Serine | PKA/PKG |
Subcellular localization
UPF0575 protein C19orf67 is expected to be targeted in the nucleus, specifically the nucleolus.[19][20]
Expression and regulation
Regulation of gene expression
The promoter region is predicted to start 1,303 bp upstream from the 5' UTR and consist of 1,447 bp, causing 144 bp to overlap with the 5' UTR.[21]
A number of transcription factors such as FOXP1, SOX5, SOX6, SOX4, and MZF1 are likely to bind with the promoter, often acting to downregulate transcription. When regarding the expression of other genes, these transcription factors typically play a role in the development of various tissues such as the heart, lung, and also take part in the differentiation of early embryonic cells, and red blood cells.
Transcriptional regulation
It is suspected that the mature mRNA of C19orf67 forms a stem loop on the 3' UTR that spans from 1,296bp to 1,350bp of the transcript.[22]
Tissue expression
In humans, UPF0575 protein C19orf67 is highly expressed in the testis and breast tissue, although it is also expressed at low levels in the stomach, cerebral cortex, thyroid gland, and salivary gland.[8][4][5]
The protein product is less abundant than most of the human proteome in many tissues.[23]
Homology
Paralogs
There are no known paralogs of UPF0575 protein C19orf67, nor are there any known paralogous domains of DUF3314 found.[2][3]
Orthologs
Orthologs of UPF0575 protein C19orf67 were found to be present among a wide variety of mammals with it being particularly well represented in rodentia and primates. Orthologs were also found in each reptilian order but were much more scarce in presence relative to mammals.[2][3] A high number and variety of ray-finned fishes were found to have orthologs while there were fewer cartilaginous fish found to have orthologs; no jawless fish could be found with orthologs.[2]
No orthologs are known to be present in birds or amphibians. No invertebrates, fungi, bacteria, or lower species have known orthologs.
BLAT and BLAST were used to create following table as a sample ortholog space for UPF0575 protein C19orf67.[2][3][24][25] This table is not a complete list of orthologs, it is meant to display the span in which there are orthologs and the diversity of those species.
| Genus and species | Common name | Accession number | Order | Divergence (MYA) | Sequence length | Identity | Similarity |
|---|---|---|---|---|---|---|---|
| Homo sapiens | Human | NP_001264307 | Primate | 0 | 358 | -- | -- |
| Galeopterus variegatus | Sunda Flying Lemur | XP_008564240.1 | Dermoptera | 82 | 358 | 85% | 89% |
| Miniopterus natalensis | Long-fingered bat | XP_016077689.1 | Chiroptera | 94 | 356 | 84% | 89% |
| Ursus maritimus | Polar bear | XP_008709937.1 | Carnivores | 94 | 358 | 85% | 89% |
| Mus musculus | House mouse | NP_898920.2 | Rodentia | 88 | 300 | 71% | 74% |
| Gekko japonicus | Gekko | XP_015270669.1 | Squamata | 320 | 331 | 49% | 63% |
| Chelonia mydas | Green Turtle | XP_007069233.1 | Testudinata | 320 | 345 | 49% | 61% |
| Alligator mississippiensis | American alligator | XP_019353135.1 | Crocodilia | 320 | 297 | 45% | 57% |
| Latimeria chalumnae | West Indian Coelacanth | XP_005995930.1 | Coelacanthiformes | 440 | 414 | 37% | 50% |
| Salmo salar | Atlantic Salmon | XP_013986580.1 | Salmoniformes | 432 | 336 | 35% | 45% |
| Danio rerio | Zebrafish | NP_001083047.1 | Cypriniformes | 432 | 344 | 32% | 44% |
| Pygocentrus nattereri | Red piranha | XP_017554468.1 | Characiformes | 432 | 348 | 32% | 43% |
Molecular evolution
UPF0575 protein C19orf67 consists of one family and there are no apparent duplications throughout the evolution of UPF0575 protein C19orf67.[2]
The DUF3314 region of the gene appears to have diverged at a slower rate relative to the rest of the gene, indicating that that region may have been undergoing purifying selection because that region played an important role in the protein.[2][24][25]
Clinical significance
In one case study, C19orf67 was one of 29 genes on chromosome 19 lost due to deletions caused by chromosomal rearrangements. The rearrangements resulted neural development issues and behavioral abnormalities, although it is not known whether C19orf67 played an active role in the resulting phenotypes.[26] In a different study, when a portion of chromosome 19 that also included C19orf67 was deleted, developmental issues such as Intrauterine growth restriction, premature birth, and muscular hypotonia, occurred.[27]
C19orf67, among many other genes, may be used as a possible marker to detect mature beta cells.[28]
References
- ↑ 1.0 1.1 1.2 1.3 "C19orf67 chromosome 19 open reading frame 67 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/646457.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 "BLAST: Basic Local Alignment Search Tool". https://blast.ncbi.nlm.nih.gov/Blast.cgi.
- ↑ 3.0 3.1 3.2 3.3 "Human BLAT Search". https://genome.ucsc.edu/cgi-bin/hgBlat?command=start.
- ↑ 4.0 4.1 github.com/gxa/atlas/graphs/contributors, EMBL-EBI Expression Atlas development team. "Expression Atlas < EMBL-EBI". http://www.ebi.ac.uk/gxa/home.
- ↑ 5.0 5.1 "77903326 - GEO Profiles - NCBI". https://www.ncbi.nlm.nih.gov/geoprofiles/77903326.
- ↑ "The DNA sequence and biology of human chromosome 19". Nature 428 (6982): 529–35. 2004. doi:10.1038/nature02399. PMID 15057824. Bibcode: 2004Natur.428..529G.
- ↑ 7.0 7.1 7.2 "Transcript: C19orf67-001 (ENST00000548523) - Domains & features - Homo sapiens - Ensembl genome browser 83" (in en-gb). http://dec2015.archive.ensembl.org/Homo_sapiens/Transcript/Domains?db=core;g=ENSG00000188032;r=19:14081619-14085762;t=ENST00000548523.
- ↑ 8.0 8.1 "Tissue expression of C19orf67 - Summary - The Human Protein Atlas". http://www.proteinatlas.org/ENSG00000188032-C19orf67/tissue.
- ↑ 9.0 9.1 Brendel, V.; Bucher, P.; Nourbakhsh, I. R.; Blaisdell, B. E.; Karlin, S. (1992-03-15). "Methods and algorithms for statistical analysis of protein sequences". Proceedings of the National Academy of Sciences of the United States of America 89 (6): 2002–2006. doi:10.1073/pnas.89.6.2002. ISSN 0027-8424. PMID 1549558. Bibcode: 1992PNAS...89.2002B.
- ↑ "Pfam: Family: DUF3314 (PF11771)". http://pfam.xfam.org/family/PF11771#tabview=tab0.
- ↑ "Database of protein domains, families and functional sites". http://prosite.expasy.org/.
- ↑ Williamson, M.P. (1994). "The structure and function of proline-rich regions in proteins". Biochemical Journal 249 (Pt 2): 249–260. doi:10.1042/bj2970249. PMID 8297327.
- ↑ Alva, Vikram; Nam, Seung-Zin; Söding, Johannes; Lupas, Andrei N. (2016-07-08). "The MPI bioinformatics Toolkit as an integrative platform for advanced protein sequence and structure analysis". Nucleic Acids Research 44 (W1): W410–W415. doi:10.1093/nar/gkw348. ISSN 0305-1048. PMID 27131380.
- ↑ Chou, Peter Y.; Fasman, Gerald D. (1974-01-15). "Prediction of protein conformation". Biochemistry 13 (2): 222–245. doi:10.1021/bi00699a002. ISSN 0006-2960. PMID 4358940.
- ↑ Charpilloz, Jean-Luc Falcone & Christophe. "TERMINUS - Welcome to terminus" (in en). http://terminus.unige.ch/.
- ↑ Fankhauser, Niklaus; Mäser, Pascal (2005-05-01). "Identification of GPI anchor attachment signals by a Kohonen self-organizing map". Bioinformatics 21 (9): 1846–1852. doi:10.1093/bioinformatics/bti299. ISSN 1367-4803. PMID 15691858.
- ↑ Blom, N.; Gammeltoft, S.; Brunak, S. (1999-12-17). "Sequence and structure-based prediction of eukaryotic protein phosphorylation sites". Journal of Molecular Biology 294 (5): 1351–1362. doi:10.1006/jmbi.1999.3310. ISSN 0022-2836. PMID 10600390.
- ↑ Blom, Nikolaj; Sicheritz-Pontén, Thomas; Gupta, Ramneek; Gammeltoft, Steen; Brunak, Søren (2004-06-01). "Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence". Proteomics 4 (6): 1633–1649. doi:10.1002/pmic.200300771. ISSN 1615-9853. PMID 15174133.
- ↑ "PSORT II server - GenScript". http://www.genscript.com/tools/psort.
- ↑ Shen, Hong-Bin; Chou, Kuo-Chen (2007-11-01). "Nuc-PLoc: a new web-server for predicting protein subnuclear localization by fusing PseAA composition and PsePSSM". Protein Engineering, Design and Selection 20 (11): 561–567. doi:10.1093/protein/gzm057. ISSN 1741-0126. PMID 17993650.
- ↑ "Genomatix - NGS Data Analysis & Personalized Medicine". https://www.genomatix.de/.
- ↑ "The Mfold Web Server | mfold.rit.albany.edu" (in en). http://unafold.rna.albany.edu/?q=mfold.
- ↑ "C19orf67 protein abundance in PaxDb" (in en). http://pax-db.org/protein/1862569.
- ↑ 24.0 24.1 EMBL-EBI. "EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI" (in en). http://www.ebi.ac.uk/Tools/psa/emboss_needle/.
- ↑ 25.0 25.1 "TimeTree :: The Timescale of Life". http://www.timetree.org/.
- ↑ Marangi, Giuseppe; Orteschi, Daniela; Vigevano, Federico; Felie, Jillian; Walsh, Christopher A.; Manzini, M. Chiara; Neri, Giovanni (2012-04-01). "Expanding the spectrum of rearrangements involving chromosome 19: A mild phenotype associated with a 19p13.12–p13.13 deletion" (in en). American Journal of Medical Genetics Part A 158A (4): 888–893. doi:10.1002/ajmg.a.35254. ISSN 1552-4833. PMID 22419660.
- ↑ Miller, David T.; Adam, Margaret P.; Aradhya, Swaroop; Biesecker, Leslie G.; Brothman, Arthur R.; Carter, Nigel P.; Church, Deanna M.; Crolla, John A. et al. (2010-05-14). "Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies". American Journal of Human Genetics 86 (5): 749–764. doi:10.1016/j.ajhg.2010.04.006. ISSN 1537-6605. PMID 20466091.
- ↑ Melton, Douglas A. & Sinisa Hrvatin, "Markers for mature beta-cells and methods of using the same", US patent 20140329704, published Nov 6, 2014
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