INAVA, sometimes referred to as hypothetical protein LOC55765, is a protein of unknown function that in humans is encoded by the INAVA gene. [5] Less common gene aliases include FLJ10901 and MGC125608.
INAVA, sometimes referred to as hypothetical protein LOC55765, is a protein of unknown function that in humans is encoded by the INAVA gene. [5] Less common gene aliases include FLJ10901 and MGC125608.
In humans, INAVA is located on the long arm of chromosome 1 at locus 1q32.1. It spans from 200,891,499 to 200,915,736 (24.238 kb) on the plus strand. [5]
INAVA is flanked by G protein-coupled receptor 25 (upstream) and maestro heat-like repeat family member 3 (MROH3P), a predicted downstream pseudogene. Ribosomal protein L34 pseudogene 6 (RPL34P6) is further upstream and kinesin family member 21B is further downstream. [5]
There are seven predicted promoters for INAVA, and experimental evidence suggests that isoform 1 and 2, the most common isoforms, are transcribed using different promoters. [6] MatInspector, a tool available through Genomatix, was used to predict transcription factor binding sites within potential promoter regions. The transcription factors that are predicted to target the anticipated promoter for isoform 1 are expressed in a range of tissues. The most common tissues of expression are the urogenital system, nervous system and bone marrow. This coincides with expression data for the INAVA protein, which is highly expressed in the kidney and bone marrow. [7] A diagram of the predicted promoter region, with highlighted transcription factor binding sites, is shown to the right. The factors that are predicted to bind to the promoter region of isoform 2 differ, and twelve of the top twenty predicted factors are expressed in blood cells and/or tissues of the cardiovascular system.
C1orf106 is expressed in a wide range of tissues. Expression data from GEO profiles is shown below. The sites of highest expression, are listed in the table. Expression is moderate in the placenta, prostate, testis, lung, salivary glands and dendritic cells. It is low in the brain, most immune cells, the adrenal gland, uterus, heart and adipocytes. [7] Expression data, from various experiments, found on GEO profiles suggests that INAVA expression is up-regulated in several cancers including: lung, ovarian, colorectal and breast.
| Tissue | Percentile rank |
|---|---|
| B lymphocytes | 90 |
| Trachea | 89 |
| Skin | 88 |
| Human bronchial epithelial cells | 88 |
| Colorectal adenocarcinoma | 87 |
| Kidney | 87 |
| Tongue | 85 |
| Pancreas | 84 |
| Appendix | 82 |
| Bone marrow | 80 |
Nine putative isoforms are produced from the INAVA gene, seven of which are predicted to encode proteins. [8] Isoform 1 and 2, shown below, are the most common isoforms.
Isoform 1, which is the longest, is accepted as the canonical isoform. It contains ten exons, which encode a protein that is 677 amino acids long, depending on the source. Some sources report that the protein is only 663 amino acids due to the use of a start codon that is forty-two nucleotides downstream. According to NCBI, this isoform has only been predicted computationally. [5] This may be because the Kozak sequence surrounding the downstream start codon is more similar to the consensus Kozak sequence as shown in the table below. Softberry was used to obtain the sequence of the predicted isoform. [9] Isoform 2 is shorter due to a truncated N-terminus. Both isoforms have an alternative polyadenylation site. [8]
miRNA-24 was identified as a microRNA that could potentially target INAVA mRNA. [10] The binding site, which is located in the 5' untranslated region is shown.
Isoform 1, diagramed below, contains a DUF3338 domain, two low complexity regions and a proline rich region. The protein is arginine and proline rich, and has a lower than average amount of asparagine and hydrophobic amino acids, specifically phenylalanine and isoleucine. [11] The isoelectric point is 9.58, and the molecular weight of the unmodified protein is 72.9 kdal. [12] The protein is not predicted to have an N-terminal signal peptide, but there are predicted nuclear localization signals (NLS) and a leucine rich nuclear export signal. [13] [14] [15]
INAVA is predicted to be highly phosphorylated. [16] [17] Phosphoylation sites predicted by PROSITE are shown in the table below. NETPhos predictions are illustrated in the diagram. Each line points to a predicted phosphorylation site, and connects to a letter which represents either serine (S), threonine (T) or tyrosine (Y).
Coiled-coils are predicted to span from residue 130-160 and 200–260. [18] The secondary composition was predicted to be about 60% random coils, 30% alpha helices and 10% beta sheets. [19]
The proteins with which the INAVA protein interacts are not well characterized. Text mining evidence suggests INAVA may interact with the following proteins: DNAJC5G, SLC7A13, PIEZO2, MUC19. [20] Experimental evidence, from a yeast two hybrid screen, suggests the INAVA protein interacts with 14-3-3 protein sigma, which is an adaptor protein. [21]
INAVA is well conserved in vertebrates as shown in the table below. Sequences were retrieved from BLAST [22] and BLAT. [23]
| Sequence | Genus and species | Common name | NCBI accession | Length(aa) | Sequence identity | Time since divergence (Mya) | |
|---|---|---|---|---|---|---|---|
| * | C1orf106 | Homo sapiens | Human | NP_060735.3 | 667 | 100% | NA |
| * | C1orf106 | Macaca fascicularis | Crab-eating macaque | XP_005540414.1 | 703 | 97% | 29.0 |
| * | LOC289399 | Rattus norvegicus | Norway rat | NP_001178750.1 | 667 | 86% | 92.3 |
| * | Predicted C1orf106 homolog | Odobenus rosmarus divergens | Walrus | XP_004392787.1 | 672 | 85% | 94.2 |
| * | C1orf106-like | Loxodonta africana | Elephant | XP_003410255.1 | 663 | 84% | 98.7 |
| * | Predicted C1orf106 homolog | Dasypus novemcinctus | Nine-banded armadillo | XP_004478752.1 | 676 | 81% | 104.2 |
| * | Predicted C1orf106 homolog | Ochotona princeps | American pika | XP_004578841.1 | 681 | 78% | 92.3 |
| * | Predicted C1orf106 homolog | Monodelphis domestica | Gray short-tailed opossum | XP_001367913.2 | 578 | 76% | 162.2 |
| * | Predicted C1orf106 homolog | Chrysemys picta bellii | Painted turtle | XP_005313167.1 | 602 | 56% | 296.0 |
| * | Predicted C1orf106 homolog | Geospiza fortis | Medium ground finch | XP_005426868.1 | 542 | 50% | 296.0 |
| * | Predicted C1orf106 homolog | Alligator mississippiensis | Alligator | XP_006278041.1 | 547 | 49% | 296.0 |
| * | Predicted C1orf106 homolog | Ficedula albicollis | Collared flycatcher | XP_005059352.1 | 542 | 49% | 296.0 |
| Predicted C1orf106 homolog | Latimeria chalumnae | West Indian Ocean coelacanth | XP_005988436.1 | 613 | 46% | 414.9 | |
| * | Predicted C1orf106 homolog | Lepisosteus oculatus | Spotted gar | XP_006628420.1 | 637 | 44% | 400.1 |
| * | FERM domain containing 4A | Xenopus (Silurana) tropicalis | Western clawed frog | XP_002935289.2 | 695 | 43% | 371.2 |
| * | Predicted C1orf106 homolog | Oreochromis niloticus | Nile tilapia | XP_005478188.1 | 576 | 40% | 400.1 |
| Predicted C1orf106 homolog | Haplochromis burtoni | Astatotilapia burtoni | XP_005914919.1 | 576 | 40% | 400.1 | |
| Predicted C1orf106 homolog | Pundamilia nyererei | Haplochromis nyererei | XP_005732720.1 | 577 | 40% | 400.1 | |
| * | LOC563192 | Danio rerio | Zebrafish | NP_001073474.1 | 612 | 37% | 400.1 |
| LOC101161145 | Oryzias latipes | Japanese rice fish | XP_004069287.1 | 612 | 33% | 400.1 | |
A graph of the sequence identity versus the time since divergence for the asterisked entries is shown below. The colors correspond to degree of relatedness (green = closely related, purple = distantly related).
Proteins that are considered to be INAVA paralogs are not consistent between databases. A multiple sequence alignment (MSA) of potentially paralogous proteins was made to determine the likelihood of a truly paralogous relationship. [24] The sequences were retrieved from a BLAST search in humans with the C1orf106 protein. The MSA suggests the proteins share a homologous domain, DUF3338, which is found in eukaryotes. A portion of the multiple sequence alignment is shown below. Apart from the DUF domain (boxed in green), there was little conservation. The DUF3338 domain does not have any extraordinary physical properties, however, one notable finding is that each of the proteins in the MSA is predicted to have two nuclear localization signals. The proteins in the MSA are all predicted to localize to the nucleus. [13] A comparison of the physical properties of the proteins was also conducted using SAPS and is shown in the table. [11]
A total of 556 single nucleotide polymorphisms (SNPs) have been identified in the gene region of INAVA, 96 of which are associated with a clinical source. [25] Rivas et al. [26] identified four SNPs, shown in the table below, that may be associated with inflammatory bowel disease and Crohn's disease. According to GeneCards, other disease associations may include multiple sclerosis and ulcerative colitis. [27]
| Residue | Change | Notes |
|---|---|---|
| 333 (rs41313912) | Tyrosine ⇒ phenylalanine | Phosphorylated, moderate conservation |
| 376 | Arginine ⇒ cysteine | Moderate conservation |
| 397 | Arginine ⇒ threonine | Not conserved |
| 554 (rs61745433) | Arginine ⇒ cysteine | Moderate conservation |
Model organisms have been used in the study of INAVA function. A conditional knockout mouse line called 5730559C18Riktm2a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. [28] Male and female animals underwent a standardized phenotypic screen [29] to determine the effects of deletion. [30] [31] [32] [33] Additional screens performed: - In-depth immunological phenotyping [34] - in-depth bone and cartilage phenotyping [35]
| Characteristic | Phenotype |
|---|---|
| All data available at. [29] [34] [35] | |
| Peripheral blood leukocytes 6 weeks | Normal |
| Insulin | Normal |
| Haematology 6 weeks | Normal |
| Homozygous viability at P14 | Normal |
| Homozygous fertility | Normal |
| Body weight | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Haematology 16 weeks | Normal |
| Peripheral blood leukocytes 16 weeks | Normal |
| Heart weight | Normal |
| Salmonella infection | Normal |
| Cytotoxic T cell function | Normal |
| Spleen immunophenotyping | Normal |
| Mesenteric lymph node immunophenotyping | Normal |
| Bone marrow immunophenotyping | Normal |
| Epidermal immune composition | Normal |
| Influenza challenge | Normal |
Chromosome 11 open reading frame one, also known as C11orf1, is a protein-coding gene. It has been found by yeast two hybrid screen to bind to SETDB1 a histone protein methyltransferase enzyme. SETDB1 has been implicated in Huntington's disease, a neurodegenerative disorder.
HIKESHI is a protein important in lung and multicellular organismal development that, in humans, is encoded by the HIKESHI gene. HIKESHI is found on chromosome 11 in humans and chromosome 7 in mice. Similar sequences (orthologs) are found in most animal and fungal species. The mouse homolog, lethal gene on chromosome 7 Rinchik 6 protein is encoded by the l7Rn6 gene.
Chromosome 20 open reading frame 111, or C20orf111, is the hypothetical protein that in humans is encoded by the C20orf111 gene. C20orf111 is also known as Perit1, HSPC207, and dJ1183I21.1. It was originally located using genomic sequencing of chromosome 20. The National Center for Biotechnology Information, or NCBI, shows that it is located at q13.11 on chromosome 20, however the genome browser at the University of California-Santa Cruz (UCSC) website shows that it is at location q13.12, and within a million base pairs of the adenosine deaminase locus. It was also found to have an increase in expression in cells undergoing hydrogen peroxide(H
2O
2)-induced apoptosis. After analyzing the amino acid content of C20orf111, it was found to be rich in serine residues.
ARMH3 or Armadillo Like Helical Domain Containing 3, also known as UPF0668 and c10orf76, is a protein that in humans is encoded by the ARMH3 gene. Its function is not currently known, but experimental evidence has suggested that it may be involved in transcriptional regulation. The protein contains a conserved proline-rich motif, suggesting that it may participate in protein-protein interactions via an SH3-binding domain, although no such interactions have been experimentally verified. The well-conserved gene appears to have emerged in Fungi approximately 1.2 billion years ago. The locus is alternatively spliced and predicted to yield five protein variants, three of which contain a protein domain of unknown function, DUF1741.
Coiled-coil domain-containing protein 138, also known as CCDC138, is a human protein encoded by the CCDC138 gene. The exact function of CCDC138 is unknown.
Cilia And Flagella Associated Protein 206 (CFAP206) is a gene that in humans encodes a protein “DUF3508”. This protein has a function that is not currently very well understood. Other known aliases are “dJ382I10.1, UPF0704 Protein C6orf165.” In humans, the gene coding sequence is 56,501 base pairs long, with an mRNA of 2,215 base pairs, and a protein sequence of 622 amino acids. The C6orf165 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, mosquito, frog, and more C6orf165 is rarely expressed in humans, with relatively high expression in brain, lungs (trachea) and testis. The molecular weight of UPF0704 is 71,193 Da and the PI is 6.38
Coiled-coil domain 47 (CCDC47) is a gene located on human chromosome 17, specifically locus 17q23.3 which encodes for the protein CCDC47. The gene has several aliases including GK001 and MSTP041. The protein itself contains coiled-coil domains, the SEEEED superfamily, a domain of unknown function (DUF1682) and a transmembrane domain. The function of the protein is unknown, but it has been proposed that CCDC47 is involved in calcium ion homeostasis and the endoplasmic reticulum overload response.
Family with sequence similarity 167, member A is a protein in humans that is encoded by the FAM167A gene located on chromosome 8. FAM167A and its paralogs are protein encoding genes containing the conserved domain DUF3259, a protein of unknown function. FAM167A has many orthologs in which the domain of unknown function is highly conserved.
Chromosome 12 Open Reading Frame 42 (C12orf42) is a protein-encoding gene in Homo sapiens.
Chromosome 21 Open Reading Frame 58 (C21orf58) is a protein that in humans is encoded by the C21orf58 gene.
Chromosome 19 open reading frame 44 is a protein that in humans is encoded by the C19orf44 gene. C19orf44 is an uncharacterized protein with an unknown function in humans. C19orf44 is non-limiting implying that the protein exists in other species besides human. The protein contains one domain of unknown function (DUF) that is highly conserved throughout its orthologs. This protein is most highly expressed in the testis and ovary, but also has significant expression in the thyroid and parathyroid. Other names for this protein include: LOC84167.
Chromosome 4 open reading frame 51 (C4orf51) is a protein which in humans is encoded by the C4orf51 gene.
Cilia- and flagella-associated protein 299 (CFAP299), is a protein that in humans is encoded by the CFAP299 gene. CFAP299 is predicted to play a role in spermatogenesis and cell apoptosis.
Chromosome 1 open reading frame 198 (C1orf198) is a protein that in humans is encoded by the C1orf198 gene. This particular gene does not have any paralogs in Homo sapiens, but many orthologs have been found throughout the Eukarya domain. C1orf198 has high levels of expression in all tissues throughout the human body, but is most highly expressed in lung, brain, and spinal cord tissues. Its function is most likely involved in lung development and hypoxia-associated events in the mitochondria, which are major consumers of oxygen in cells and are severely affected by decreases in available cellular oxygen.
Chromosome 9 open reading frame 50 is a protein that in humans is encoded by the C9orf50 gene. C9orf50 has one other known alias, FLJ35803. In humans the gene coding sequence is 10,051 base pairs long, transcribing an mRNA of 1,624 bases that encodes a 431 amino acid protein.
Chromosome 1 open reading frame 185, also known as C1orf185, is a protein that in humans is encoded by the C1orf185 gene. In humans, C1orf185 is a lowly expressed protein that has been found to be occasionally expressed in the circulatory system.
C14orf119 is a protein that in humans is encoded by the c14orf119 gene. The c14orf119 protein is predicted to be localized in the nucleus. Additionally, c14orf119 expression is decreased in individuals with systemic lupus erythematosus (SLE) when compared with healthy individual and is increased in individuals with various types of lymphomas when compared to healthy individuals.
Coiled-coil domain containing 121 (CCDC121) is a protein encoded by the CCDC121 gene in humans. CCDC121 is located on the minus strand of chromosome 2 and encodes three protein isoforms. All isoforms of CCDC121 contain a domain of unknown function referred to as DUF4515 or pfam14988.
C6orf136 is a protein in humans encoded by the C6orf136 gene. The gene is conserved in mammals, mollusks, as well some porifera. While the function of the gene is currently unknown, C6orf136 has been shown to be hypermethylated in response to FOXM1 expression in Head Neck Squamous Cell Carcinoma (HNSCC) tissue cells. Additionally, elevated expression of C6orf136 has been associated with improved survival rates in patients with bladder cancer. C6orf136 has three known isoforms.
Coiled-Coil Domain Containing 190, also known as C1orf110, the Chromosome 1 Open Reading Frame 110, MGC48998 and CCDC190, is found to be a protein coding gene widely expressed in vertebrates. RNA-seq gene expression profile shows that this gene selectively expressed in different organs of human body like lung brain and heart. The expression product of c1orf110 is often called Coiled-coil domain-containing protein 190 with a size of 302 aa. It may get the name because a coiled-coil domain is found from position 14 to 72. At least 6 spliced variants of its mRNA and 3 isoforms of this protein can be identified, which is caused by alternative splicing in human.