IGSF6 is a protein that in humans is encoded by the ''IGSF6'' gene. IGSF6 Phyre Structure

Overview

In humans, the immunoglobulin superfamily member 6 (IGSF6) gene with alias DORA encodes CD8 protein IGSF6 (24 kDA) with orthologs in

mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

birds Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

reptiles Reptiles, as most commonly defined are the animals in the Class (biology), class Reptilia ( ), a paraphyletic grouping comprising all sauropsid, sauropsids except birds. Living reptiles comprise turtles, crocodilians, Squamata, squamates (lizar ...

, and bony fishes. IGSF6 is located on the complement strand of chromosome 16 (16p12.2) spanning 13059 base pairs and is located entirely within an

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

of the gene METTL9. IGSF6 is predicted to be an integral component of the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

and contribute to

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

. 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 Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...

(IBD). However, there was no association with

single nucleotide polymorphisms In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

(SNPs) and IBD in patients with the disease.

Gene

A common alias for IGSF6 is downregulated by activation (DORA). The cytogenic location is on

chromosome 16 Chromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs (the building material of DNA) and represents just under 3% of the total DNA in cell ...

(16p12.2). IGSF6 has 6

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

total. The span of the gene is 13059 base pairs.

Proteins

The theoretical

isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). However, pI is also u ...

(pI) and

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

(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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

half has a lower pI than the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

half. IGSF6 is neutral at 8.93 and would be negative around 7. 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 Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

Structure

The secondary structure of IGSF6 is predicted to have regions of coils, strands, and alpha helices. The most pronounced

helix A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helices, ...

regions occur from amino acids 149-178 and amino acids 197-218. I-Tasser IGSF6

IGSF6 contains a

transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...

from amino acids 154 to 176. The predicted

disulfide bonds In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

were found using DiANNA. DiANNA disulfide bonds

Gene Level Regulation

Expression Pattern

IGSF6 is highly expressed in

white blood cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

and

secondary lymphoid organs The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...

including the

lymph nodes A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...

and

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

. The mRNA abundance across 20 human tissues is low. The micro-array assessed tissue expression patterns showed high expression in

ganglia A ganglion is a group of neuron cell bodies in the peripheral nervous system. In the somatic nervous system this includes dorsal root ganglia and trigeminal ganglia among a few others. In the autonomic nervous system there are both sympatheti ...

monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...

, and

myeloid tissue Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...

. ''In situ'' hybridization showed that the regulation of IGSF6 was low and ubiquitously expressed in the mouse brain. Proteins are localized in the human

testis A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...

and

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

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

. IGSF6 has a

signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-ter ...

from amino acids 17 to 32. 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. 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. IGSF6 has a

SUMOylation In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (sometimes w ...

site at amino acid 190.

Homology and Evolution

Paralogs

The only

paralog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

of IGSF6 is T cell receptor beta variable 28 (TCRBV28). 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. TRBV28 is a quickly evolving gene, as it evolves similarly to fibrinogen alpha. IGSF6 Paralog Table

Orthologs

The

of IGSF6 were found through NCBI protein and sorted by median date of divergence and sequence identity to the human 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 Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

amphibians Amphibians are four-limbed and ectothermic vertebrates of the class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terrestrial, fossorial, arbore ...

, and

fish Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% of li ...

proteins have an average sequence similarity to the human protein of 52%, 50%, 50%, and 45% respectively. IGSF6 is a fast-evolving gene because it evolves similarly to fibrinogen alpha. IGSF6 Orthologs

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. IGSF6 Interacting Proteins

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

. IGSF6 has been researched as a possible indicator of inflammatory bowel disease (IBD) susceptibility. However, there was no association with single nucleotide polymorphisms (SNPs) and IBD in patients with the disease.

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 Esophageal cancer is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain when swallowing, a hoarse voi ...

Multiple Sclerosis

IGSF6 was found to be upregulated in the

myeloid cells A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases). Structure When stained with the usual dyes, the cytoplasm is distinctly basophilic ...

function pathway in patients with

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

, a chronic autoimmune demyelinating disease of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

.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

References

{{reflist Genes on human chromosome 16