C5orf36

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C5orf36 is a protein that in humans is encoded by the gene of the same name, located on chromosome 5, 5q15. It is a possible risk factor in Type II Diabetes, and associated with high levels of glucose in the blood. It is a relatively fast mutating gene, compared to other coding genes. There is however one region which is highly conserved across the species that have the gene, known as DUF4495. It is predicted to be a protein that travels between the nucleus and the cytoplasm.

General information

File:C5orf36 isoforms.png
The Isoforms of C5orf36

C5orf36 is gene that appears to be a genetic factor that increases the risk of Type II Diabetes, possibly by increasing the level of blood glucose levels.[1] It has also been identified as a possible oncogene.[2] C5orf36 has one common alias KIAA0825. The gene is about 478 kb long and contains 22 exons. It produces 10 different variants: 9 alternatively spliced, and one un-spliced version. The longest experimentally confirmed mRNA is 7240 bp long and produces a protein 1275 amino acids long.[3] The protein is predicted to weigh about 147.8kDal. It has orthologs in most animals including Aplysia californica, but is not found outside animals with the possible exception of Plasmodiophora brassicae.

Protein information

The protein has a predicted weight of 147.8 kDal.[4][5] It does not contain a known nuclear localization signal but does contain a nuclear export signal.[6] The subcellular localization for the protein is predicted to be the nucleus and the cytoplasm.[7] This suggests that the protein might shuttle back and forth across the nuclear membrane.

Secondary structure

File:C5orf36 Predicted Tertiary Structure.png
This is a 3-D Prediction created by I-TASSER. The green indicates the conserved DUF4495.

Several programs suggest that the secondary structure of the protein is mainly helices with only a few beta sheets.[8][9][10][11] Analysis of protein composition also suggests that the protein has relatively low levels of glycine.[12] This could suggest a fairly rigid structure relative to other proteins. The tertiary structure is harder to predict due to the size of the protein, partially due to its size. The 3-D structure shown shows a prediction made by I-TASSER. This is a possible strture with a C-score of -1.06 on a scale from -5 to 1 (in which the higher the number the greater the confidence).[13][14][15] This predicted structure indicates there are two main parts, and it is possible they interact depending on the state of the protein (e.g. whether or not it's phosphorylated).

Expression

File:C5orf36 mRNA expression data.png
mRNA expression data from the Human Protein Atlas, calculated as transcripts per million (TPM).
File:C5orf36 Protein expression.png
This shows the expression levels of C5orf36 in human tissue. It is provided by the Human Protein Atlas.

The mRNA for C5orf36 is expressed at relatively low rates in comparison to other mRNAs.[16] The protein however is expressed at relatively high rates, especially in parts of the brain as well as adrenal glands and the thyroid.[17] This would suggest that the protein is not readily degraded and remains in the cell for long periods of time, such that continuous transcription of the DNA into mRNA is unnecessary. In an expression profile done of the peripheral blood of patients with B-lymphocytic leukemia C5orf36 has slightly higher levels in patients with chronic B-lymphocytic leukemia as compared to the healthy patients.[18] Another expression profile shows that C5orf36 is expressed at lower levels in patients with Type II Diabetes compared with healthy patients.[19] No current finding suggest that there is alternative expression of different isoforms in different tissues.

Regulation

Analysis of the promoter offers some insight into the expression of C5orf36.[20] One possible regulator found is the NeuroD1 transcription factor. This factor is an important regulator for the insulin gene, and a mutation in this gene can lead to Type II diabetes.[21] This could explain why C5orf36 is expressed at lower levels in patients with Type II diabetes. Another possible transcription factor is the Myeloid zinc finger 1 factor, which is tied to myeloid leukemia, because it delays apoptosis of cells in the presence of retinoic acid.[22] There are also several places where Vertebrate SMAD family transcription factors can bind. These transcription factors are thought to be responsible for nucleocytoplasmic dynamics.[23] This means that these SMAD transcription factors could effect C5orf36, because subcellular localization suggests it shuttles across the nuclear envelope.

Function

There are two proteins found to interact with C5orf36. One is One is Interleukin enhancer-binding factor 3.[24] ILF3 is a factor that complexes with other proteins and regulates gene expression and stabilizes mRNAs.[25] The other is the Amyloid-beta precursor protein.[26] This protein is an integral membrane protein found most commonly in the synapses of neurons. Neither of these proteins is well enough understood to indicate for certain the role of C5orf36 in human cells. They however suggest that C5orf36 could serve a variety of roles in different parts of the cell.

Orthology

C5orf36 orthologs can be found in virtually all animals, but cannot be found in plants, bacteria, or protozoa. It is mostly highly conserved in vertebrates especially mammals, but genes that contain region similar to DUF4495 region can be found in California sea hare, generally one of the most simple animal. The size especially in mammals is well conserved sticking very close to between 1250 and 1300 amino acids long. This suggests that the protein wraps around on itself forming important structures for its function.

There were no paralogs found of the gene C5orf36 in humans or in any other species.

References

  1. ↑ Li, Jing; Wei, Jiachen; Xu, Pengcheng; Yan, Mengdan; Li, Jingjie; Chen, Zhengshuai; Jin, Tianbo (19 December 2016). "Impact of diabetes-related gene polymorphisms on the clinical characteristics of type 2 diabetes Chinese Han population". Oncotarget. doi:10.18632/oncotarget.13399.
  2. ↑ Delgado, Ana Paula; Brandao, Pamela; Chapado, Maria Julia; Hamid, Sheilin; Narayanan, Ramaswamy (7/1/2014). "Opening Reading Frames Associated with Cancer in the Dark Matter of the Human Genome". Cancer Genomics - Proteomics. 11 (4): 201–213. Check date values in: |date= (help)
  3. ↑ "Database Resources of the National Center for Biotechnology Information". Nucleic Acids Research. 45 (D1): D12–D17. 4 January 2017. doi:10.1093/nar/gkw1071. PMC 5210554. PMID 27899561.
  4. ↑ Brendel, V; Bucher, P; Nourbakhsh, I. R; Blaisdell, B. E; Karlin, S (1992). "Methods and algorithms for statistical analysis of protein sequences". Proc. Natl. Acad. Sci. U.S.A. 89: 2002–2006. Bibcode:1992PNAS...89.2002B.
  5. ↑ Brendel, Volker. "SDSC Biology Workbench". workbench.sdsc.edu. Department of Mathematics, Stanford University, CA. Retrieved 17 April 2017.
  6. ↑ la Cour, Tanja; Kiemer, Lars; Mølgaard, Anne; Gupta, Ramneek; Skriver, Karen; Brunak, Søren (2004). "Analysis and prediction of leucine-rich nuclear export signals". Protein Eng. Des. Sel. 17 (6): 527–536.
  7. ↑ Nakai, K; Horton, P (January 1999). "PSORT: a program for detecting sorting signals in proteins and predicting their subcellular localization". Trends in Biochemical Sciences. 24 (1): 34–6. PMID 10087920.
  8. ↑ Bigelow, H. R. (28 April 2004). "Predicting transmembrane beta-barrels in proteomes". Nucleic Acids Research. 32 (8): 2566–2577. doi:10.1093/nar/gkh580.
  9. ↑ Rost, B; Yachdav, G; Liu, J (2004). "The Predict Protein server". Nucleic Acids Res. 32: 321–326.
  10. ↑ Garnier, J; Osguthorpe, DJ; Robson, B (25 March 1978). "Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins". Journal of Molecular Biology. 120 (1): 97–120. PMID 642007.
  11. ↑ Burgess, A. W.; Ponnuswamy, P. K.; Scheraga, H. A. (1974). "Analysis of Conformations of Amino Acid Residues and Prediction of Backbone Topography in Proteins". Israel Journal of Chemistry. 12 (1–2): 239–286. doi:10.1002/ijch.197400022.
  12. ↑ Brendel, V; Bucher, P; Nourbakhsh, IR; Blaisdell, BE; Karlin, S (15 March 1992). "Methods and algorithms for statistical analysis of protein sequences". Proceedings of the National Academy of Sciences of the United States of America. 89 (6): 2002–6. Bibcode:1992PNAS...89.2002B. PMID 1549558.
  13. ↑ Zhang, Yang (2008). "I-TASSER server for protein 3D structure prediction". BMC Bioinformatics. 9 (1): 40. doi:10.1186/1471-2105-9-40.
  14. ↑ Roy, Ambrish; Kucukural, Alper; Zhang, Yang (25 March 2010). "I-TASSER: a unified platform for automated protein structure and function prediction". Nature Protocols. 5 (4): 725–738. doi:10.1038/nprot.2010.5.
  15. ↑ Yang, Jianyi; Yan, Renxiang; Roy, Ambrish; Xu, Dong; Poisson, Jonathan; Zhang, Yang (30 December 2014). "The I-TASSER Suite: protein structure and function prediction". Nature Methods. 12 (1): 7–8. doi:10.1038/nmeth.3213. PMID 25549265.
  16. ↑ Uhlen, M.; Fagerberg, L.; Hallstrom, B. M.; Lindskog, C.; Oksvold, P.; Mardinoglu, A.; Sivertsson, A.; Kampf, C.; Sjostedt, E.; Asplund, A.; Olsson, I.; Edlund, K.; Lundberg, E.; Navani, S.; Szigyarto, C. A.-K.; Odeberg, J.; Djureinovic, D.; Takanen, J. O.; Hober, S.; Alm, T.; Edqvist, P.-H.; Berling, H.; Tegel, H.; Mulder, J.; Rockberg, J.; Nilsson, P.; Schwenk, J. M.; Hamsten, M.; von Feilitzen, K.; Forsberg, M.; Persson, L.; Johansson, F.; Zwahlen, M.; von Heijne, G.; Nielsen, J.; Ponten, F. (22 January 2015). "Tissue-based map of the human proteome". Science. 347 (6220): 1260419–1260419. doi:10.1126/science.1260419.
  17. ↑ Uhlen, M.; Fagerberg, L.; Hallstrom, B. M.; Lindskog, C.; Oksvold, P.; Mardinoglu, A.; Sivertsson, A.; Kampf, C.; Sjostedt, E.; Asplund, A.; Olsson, I.; Edlund, K.; Lundberg, E.; Navani, S.; Szigyarto, C. A.-K.; Odeberg, J.; Djureinovic, D.; Takanen, J. O.; Hober, S.; Alm, T.; Edqvist, P.-H.; Berling, H.; Tegel, H.; Mulder, J.; Rockberg, J.; Nilsson, P.; Schwenk, J. M.; Hamsten, M.; von Feilitzen, K.; Forsberg, M.; Persson, L.; Johansson, F.; Zwahlen, M.; von Heijne, G.; Nielsen, J.; Ponten, F. (22 January 2015). "Tissue-based map of the human proteome". Science. 347 (6220): 1260419–1260419. doi:10.1126/science.1260419.
  18. ↑ Vargova, K.; Curik, N.; Burda, P.; Basova, P.; Kulvait, V.; Pospisil, V.; Savvulidi, F.; Kokavec, J.; Necas, E.; Berkova, A.; Obrtlikova, P.; Karban, J.; Mraz, M.; Pospisilova, S.; Mayer, J.; Trneny, M.; Zavadil, J.; Stopka, T. (4 February 2011). "MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia". Blood. 117 (14): 3816–3825. doi:10.1182/blood-2010-05-285064.
  19. ↑ Misu, Hirofumi; Takamura, Toshinari; Takayama, Hiroaki; Hayashi, Hiroto; Matsuzawa-Nagata, Naoto; Kurita, Seiichiro; Ishikura, Kazuhide; Ando, Hitoshi; Takeshita, Yumie; Ota, Tsuguhito; Sakurai, Masaru; Yamashita, Tatsuya; Mizukoshi, Eishiro; Yamashita, Taro; Honda, Masao; Miyamoto, Ken-ichi; Kubota, Tetsuya; Kubota, Naoto; Kadowaki, Takashi; Kim, Han-Jong; Lee, In-kyu; Minokoshi, Yasuhiko; Saito, Yoshiro; Takahashi, Kazuhiko; Yamada, Yoshihiro; Takakura, Nobuyuki; Kaneko, Shuichi (November 2010). "A Liver-Derived Secretory Protein, Selenoprotein P, Causes Insulin Resistance". Cell Metabolism. 12 (5): 483–495. doi:10.1016/j.cmet.2010.09.015.
  20. ↑ "Genomatix". Genomatix. Retrieved 7 May 2017.
  21. ↑ Sharma, Arun; Moore, Melissa; Marcora, Edoardo; Lee, Jacqueline E.; Qiu, Yi; Samaras, Susan; Stein, Roland (1 January 1999). "The NeuroD1/BETA2 Sequences Essential for Insulin Gene Transcription Colocalize with Those Necessary for Neurogenesis and p300/CREB Binding Protein Binding". Molecular and Cellular Biology. 19 (1): 704–713. doi:10.1128/MCB.19.1.704. PMID 83927.
  22. ↑ Robertson, KA; Hill, DP; Kelley, MR; Tritt, R; Crum, B; Van Epps, S; Srour, E; Rice, S; Hromas, R (May 1998). "The myeloid zinc finger gene (MZF-1) delays retinoic acid-induced apoptosis and differentiation in myeloid leukemia cells". Leukemia. 12 (5): 690–8. PMID 9593266.
  23. ↑ Massague, J. (1 December 2005). "Smad transcription factors". Genes & Development. 19 (23): 2783–2810. doi:10.1101/gad.1350705.
  24. ↑ Chu, L; Su, MY; Maggi LB, Jr; Lu, L; Mullins, C; Crosby, S; Huang, G; Chng, WJ; Vij, R; Tomasson, MH (August 2012). "Multiple myeloma-associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress". The Journal of Clinical Investigation. 122 (8): 2793–806. PMID 22751105.
  25. ↑ Chaumet, Alexandre; Castella, Sandrine; Gasmi, Laïla; Fradin, Aurélie; Clodic, Gilles; Bolbach, Gérard; Poulhe, Robert; Denoulet, Philippe; Larcher, Jean-Christophe (June 2013). "Proteomic analysis of interleukin enhancer binding factor 3 (Ilf3) and nuclear factor 90 (NF90) interactome". Biochimie. 95 (6): 1146–1157. doi:10.1016/j.biochi.2013.01.004.
  26. ↑ Oláh, J; Vincze, O; Virók, D; Simon, D; Bozsó, Z; Tõkési, N; Horváth, I; Hlavanda, E; Kovács, J; Magyar, A; Szũcs, M; Orosz, F; Penke, B; Ovádi, J (30 September 2011). "Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein". The Journal of Biological Chemistry. 286 (39): 34088–100. PMID 21832049.
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