IGSF6

In humans, the immunoglobulin superfamily member 6 (IGSF6) gene with alias DORA encodes CD8 protein IGSF6 (24 kDA) with orthologs in mammals, birds, reptiles, and bony fishes.NCBI (National Library of Medicine) [https://www.ncbi.nlm.nih.gov/nuccore/NM_005849.4]. IGSF6 is located on the complement strand of chromosome 16 (16p12.2) spanning 13059 base pairs and is located entirely within an intron of the gene METTL9.NCBI (National Library of Medicine IGSF6 [https://www.ncbi.nlm.nih.gov/gene/10261]. IGSF6 is predicted to be an integral component of the plasma membrane and contribute to immune response.NCBI (National Library of Medicine) Gene Entry on IGSF6 [https://www.ncbi.nlm.nih.gov/gene/10261]. It is also predicted to be involved in cell surface receptor signaling and enable transmembrane signaling receptor activity. IGSF6 gene was localized to a locus associated with inflammatory bowel disease (IBD). However, there was no association with single nucleotide polymorphisms (SNPs) and IBD in patients with the disease.King, K., Moody, A., Fisher, S. A., Mirza, M. M., Cuthbert, A. P., Hampe, J., Sutherland-Craggs, A., Sanderson, J., MacPherson, A. J., Forbes, A., Mansfield, J., Schreiber, S., Lewis, C. M., & Mathew, C. G. (2003). Genetic variation in the IGSF6 gene and lack of association with inflammatory bowel disease. European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics, 30(3), 187–190. https://doi.org/10.1046/j.1365-2370.2003.00387.x

A common alias for IGSF6 is downregulated by activation (DORA). The cytogenic location is on chromosome 16 (16p12.2). IGSF6 has 6 exons total.NCBI IGSF6 mRNA [https://www.ncbi.nlm.nih.gov/nuccore/NM_005849.4]. The span of the gene is 13059 base pairs.UCSC Genome Browser IGSF6 [https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr16%3A21639550%2D21652608&hgsid=1415158853_28f2D9TBJabgAH4nzjuFcnHvFBm5].

The theoretical isoelectric point (pI) and molecular weight (mw) for the IGSF6 protein are 8.9 and 27 kDa, respectively, before any modification. The pI of the protein is not consistent throughout, as the N-terminal half has a lower pI than the C-terminal half. IGSF6 is neutral at 8.93 and would be negative around 7.ExPASy pI/Mw for IGSF6 [https://web.expasy.org/cgi-bin/compute_pi/pi_tool]{{Dead link|date=October 2022 |bot=InternetArchiveBot |fix-attempted=yes }}.

Eukaryotic Linear Motif (ELM) was used to find protein Motifs. The list ELM provided was after globular domain filtering, structural filtering, and context filtering. The four Motifs shown are organized by probability and are conserved in mammalian orthologs.ELM Prediction of IGSF6 Protein [http://elm.eu.org/].

File:ELM Motifs.png

The secondary structure of IGSF6 is predicted to have regions of coils, strands, and alpha helices.I-Tasser Results for IGSF6 [https://seq2fun.dcmb.med.umich.edu//I-TASSER/output/S695291/]{{Dead link|date=January 2023 |bot=InternetArchiveBot |fix-attempted=yes }}. The most pronounced helix regions occur from amino acids 149-178 and amino acids 197-218.I-Tasser Results for IGSF6 [https://seq2fun.dcmb.med.umich.edu//I-TASSER/output/S695291/]{{Dead link|date=January 2023 |bot=InternetArchiveBot |fix-attempted=yes }}.Wei Zheng, Chengxin Zhang, Yang Li, Robin Pearce, Eric W. Bell, Yang Zhang. Folding non-homology proteins by coupling deep-learning contact maps with I-TASSER assembly simulations. Cell Reports Methods, 1: 100014 (2021).Chengxin Zhang, Peter L. Freddolino, and Yang Zhang. COFACTOR: improved protein function prediction by combining structure, sequence and protein-protein interaction information. Nucleic Acids Research, 45: W291-299 (2017).Jianyi Yang, Yang Zhang. I-TASSER server: new development for protein structure and function predictions, Nucleic Acids Research, 43: W174-W181, 2015.

File:I-Tasser IGSF6.png IGSF6 contains a transmembrane domain from amino acids 154 to 176.SAPS analysis of IGSF6 [https://www.ebi.ac.uk/Tools/services/web/toolresult.ebi?jobId=saps-I20220722-035911-0562-77992316-p2m]. The predicted disulfide bonds were found using DiANNA.DiANNA predicted disulfide bonds for IGSF6 [http://clavius.bc.edu/~clotelab/DiANNA/] {{Webarchive|url=https://web.archive.org/web/20220724010112/http://clavius.bc.edu/~clotelab/DiANNA/ |date=2022-07-24 }}.

File:DiANNA disulfide bonds.png

IGSF6 is highly expressed in white blood cells and secondary lymphoid organs including the lymph nodes and spleen.NCBI Gene Entry on IGSF6 [https://www.ncbi.nlm.nih.gov/gene/10261].

The mRNA abundance across 20 human tissues is low.NCBI Gene Entry on IGSF6 [https://www.ncbi.nlm.nih.gov/gene/10261]. The micro-array assessed tissue expression patterns showed high expression in ganglia, monocytes, and myeloid tissue.NCBI GeoProfiles of IGSF6 [https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS596:206420_at]. In situ hybridization showed that the regulation of IGSF6 was low and ubiquitously expressed in the mouse brain.Allen Brain Atlas [https://mouse.brain-map.org/gene/show/56493]. Proteins are localized in the human testis and thyroid.ThermoFischer Scientific IGSF6 Antibody [https://www.thermofisher.com/antibody/primary/target/igsf6].

The promotor region and transcription factors are shown in the promotor diagram. The transcription factors shown were highly conserved in animal orthologs of IGSF6.

File:IGSF6 Promotor Diagram.png

The IGSF6 protein is predicted to be in the plasma membrane.PSORT II Prediction of IGSF6 [https://psort.hgc.jp/form2.html].DeepLoc IGSF6 Prediction [https://services.healthtech.dtu.dk/service.php?DeepLoc-1.0]. IGSF6 has a signal peptide from amino acids 17 to 32.NCBI (National Library of Medicine) [https://www.ncbi.nlm.nih.gov/nuccore/NM_005849.4]. IGSF6 has post-translational modifications including phosphorylation sites and lysine acetylation sites. The phosphorylation sites at amino acid positions 3, 5, 91, 193, 198, 222, and 236, and these sites are important in enzymatic function.GPS Phosphorylation Sites [http://gps.biocuckoo.cn/]. The lysine acetylation sites are at amino acids 187, 195, 196, 213, and 224, and they are important in gene expression, protein–protein interactions, and protein processing and degradation.GPS-Pail Prediction of Acetylation [http://pail.biocuckoo.org/].Zencheck, W. D., Xiao, H., & Weiss, L. M. (2012). Lysine post-translational modifications and the cytoskeleton. Essays in biochemistry, 52, 135–145. https://doi.org/10.1042/bse0520135 IGSF6 has a SUMOylation site at amino acid 190.GPS-SUMO Prediction of SUMOylation sites [http://sumosp.biocuckoo.org/] {{Webarchive|url=https://web.archive.org/web/20130510131129/http://sumosp.biocuckoo.org/ |date=2013-05-10 }}.

The only paralog of IGSF6 is T cell receptor beta variable 28 (TCRBV28).NCBI Blast [https://blast.ncbi.nlm.nih.gov/Blast.cgi]. Birds are the most distant organism that TRBV28 is found in, so the gene duplication to create the paralog occurred about 320 million years ago.TimeTree Divergence of Humans and Birds [http://www.timetree.org/]. TRBV28 is a quickly evolving gene, as it evolves similarly to fibrinogen alpha.

File:IGSF6 Paralog Table.png

The orthologs of IGSF6 were found through NCBI protein and sorted by median date of divergence and sequence identity to the human protein.NCBI Protein [https://www.ncbi.nlm.nih.gov/protein/]. The IGSF6 protein is found only in vertebrates with the H. sapiens IGSF6 protein being most distantly related to the fish IGSF6 protein. The human IGSF6 protein is most closely related to the IGSF6 protein of other mammals. Aves, reptiles, amphibians, and fish proteins have an average sequence similarity to the human protein of 52%, 50%, 50%, and 45% respectively.Emboss Needle Alignment [https://www.ebi.ac.uk/Tools/psa/emboss_needle/]. IGSF6 is a fast-evolving gene because it evolves similarly to fibrinogen alpha.

File:IGSF6 Orthologs.png

File:IGSF6 Evolution Rate Graph.png

The most likely protein to interact with IGSF6 is methyltransferase-like protein 9 (METTL9) because IGSF6 is in an intron of METTL9. Most of the proteins that IGSF6 interacts with have immunological functions.String DB view of IGSF6 Protein interactions [https://string-db.org/network/9606.ENSP00000268389].

File:IGSF6 Interacting Proteins.png

IGSF6 is predicted to be involved in immunological response. Its high expression in white blood cells and secondary lymphoid organs support this. IGSF6 has been associated with several diseases and conditions.

The human IGSF6 gene was localized to a locus associated with inflammatory bowel disease. IGSF6 has been researched as a possible indicator of inflammatory bowel disease (IBD) susceptibility.Bates, E. E., Kissenpfennig, A., Péronne, C., Mattei, M. G., Fossiez, F., Malissen, B., & Lebecque, S. (2000). The mouse and human IGSF6 (DORA) genes map to the inflammatory bowel disease 1 locus and are embedded in an intron of a gene of unknown function. Immunogenetics, 52(1-2), 112–120. https://doi.org/10.1007/s002510000259 However, there was no association with single nucleotide polymorphisms (SNPs) and IBD in patients with the disease.King, K., Moody, A., Fisher, S. A., Mirza, M. M., Cuthbert, A. P., Hampe, J., Sutherland-Craggs, A., Sanderson, J., MacPherson, A. J., Forbes, A., Mansfield, J., Schreiber, S., Lewis, C. M., & Mathew, C. G. (2003). Genetic variation in the IGSF6 gene and lack of association with inflammatory bowel disease. European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics, 30(3), 187–190. https://doi.org/10.1046/j.1365-2370.2003.00387.x

The combined expression of IGSF6 and nine other genes was significantly related to the overall and disease-free survival in patients with esophageal squamous cell carcinoma.Guo, J., Liu, T., Shi, X., Mao, B., Zhang, J., Zhang, H., & Xian, L. (2020). Transcriptional profile of immune microenvironment and their prediction role for the prognosis of esophageal squamous cell carcinoma. Journal of Clinical Oncology, 38(4), 416–416. https://doi.org/10.1200/jco.2020.38.4_suppl.416

IGSF6 was found to be upregulated in the myeloid cells function pathway in patients with multiple sclerosis, a chronic autoimmune demyelinating disease of the central nervous system.Ivanova, M., Voronkova, A., Sukhorukov, V., & Zakharova, M. (2021). Different neuroinflammatory gene expression profiles in highly active and benign multiple sclerosis. Journal of Neuroimmunology, 358, 577650. https://doi.org/10.1016/j.jneuroim.2021.577650

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Category:Genes on human chromosome 16