IGSF6

IGSF6 is a protein that in humans is encoded by the IGSF6 gene.^[5][6]

Predicted IGSF6 Model from Phyre Viewed with iCN3D.

IGSF6
Identifiers
Aliases	IGSF6, DORA, immunoglobulin superfamily member 6
External IDs	OMIM: 606222; MGI: 1891393; HomoloGene: 36189; GeneCards: IGSF6; OMA:IGSF6 - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p12.2 Start 21,639,550 bp[1] End 21,652,608 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 F2 Start 120,663,290 bp[2] End 120,673,795 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte blood granulocyte appendix spleen lymph node bone marrow cell placenta testicle rectum Top expressed in granulocyte spleen bone marrow liver ileum jejunum lung zone of skin thymus colon More reference expression data BioGPS n/a
Gene ontology Molecular function transmembrane signaling receptor activity Cellular component integral component of membrane integral component of plasma membrane membrane Biological process cell surface receptor signaling pathway immune response Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10261 80719 Ensembl ENSG00000140749 ENSMUSG00000035004 UniProt O95976 P0C6B7 RefSeq (mRNA) NM_005849 NM_030691 RefSeq (protein) NP_005840 NP_109616 Location (UCSC) Chr 16: 21.64 – 21.65 Mb Chr 7: 120.66 – 120.67 Mb PubMed search [3] [4]
Wikidata
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Overview

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.^[7] 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.^[8] IGSF6 is predicted to be an integral component of the plasma membrane and contribute to immune response.^[9] 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.^[10]

Gene

A common alias for IGSF6 is downregulated by activation (DORA). The cytogenic location is on chromosome 16 (16p12.2). IGSF6 has 6 exons total.^[11] The span of the gene is 13059 base pairs.^[12]

Proteins

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.^[13]

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.^[14]

ELM Binding Motifs for IGSF6.

Structure

The secondary structure of IGSF6 is predicted to have regions of coils, strands, and alpha helices.^[15] The most pronounced helix regions occur from amino acids 149-178 and amino acids 197-218.^{[16][17][18][19]}

I-TASSER predicted three-dimensional structure of IGSF6.

IGSF6 contains a transmembrane domain from amino acids 154 to 176.^[20] The predicted disulfide bonds were found using DiANNA.^[21]

Predicted disulfide bonding patterns from DiANNA.

Gene Level Regulation

Expression Pattern

IGSF6 is highly expressed in white blood cells and secondary lymphoid organs including the lymph nodes and spleen.^[22] The mRNA abundance across 20 human tissues is low.^[23] The micro-array assessed tissue expression patterns showed high expression in ganglia, monocytes, and myeloid tissue.^[24] In situ hybridization showed that the regulation of IGSF6 was low and ubiquitously expressed in the mouse brain.^[25] Proteins are localized in the human testis and thyroid.^[26]

Promotor and Transcription Factors

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

IGSF6 Promotor Diagram.

Protein Level Regulation

The IGSF6 protein is predicted to be in the plasma membrane.^[27][28] IGSF6 has a signal peptide from amino acids 17 to 32.^[29] 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.^[30] 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.^[31][32] IGSF6 has a SUMOylation site at amino acid 190.^[33]

Homology and Evolution

Paralogs

The only paralog of IGSF6 is T cell receptor beta variable 28 (TCRBV28).^[34] 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.^[35] TRBV28 is a quickly evolving gene, as it evolves similarly to fibrinogen alpha.

IGSF6 Paralog Table.

Orthologs

The orthologs of IGSF6 were found through NCBI protein and sorted by median date of divergence and sequence identity to the human protein.^[36] 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.^[37] IGSF6 is a fast-evolving gene because it evolves similarly to fibrinogen alpha.

IGSF6 Ortholog Table.

Graph of IGSF6 Showing Rate of Evolution Compared to Other Genes and Proteins.

Interacting Proteins

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.^[38]

Proteins that IGSF6 Interacts With.

Clinical Significance

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.

Inflammatory Bowel Disease

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.^[39] However, there was no association with single nucleotide polymorphisms (SNPs) and IBD in patients with the disease.^[40]

Esophageal Squamous Cell Carcinoma

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.^[41]

Multiple Sclerosis

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.^[42]