Transmembrane protein 169 (TMEM169) in humans is encoded by TMEM169 gene. [1] The aliases of TMEM169 include FLJ34263, DKFZp781L2456, and LOC92691. [2] TMEM169 has the highest expression in the brain, particularly the fetal brain. [1] TMEM169 has homologs mammals, reptiles, amphibians, birds, fish, chordates and invertebrates. The most distantly related homolog of TMEM169 is Anopheles albimanus. [3]
TMEM169 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | TMEM169 , transmembrane protein 169 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | MGI: 2442781; HomoloGene: 16305; GeneCards: TMEM169; OMA:TMEM169 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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The gene is located on human chromosome 2(2q35) and spans 20,918 bases (216,081,866-216,102,783) [8] on the + strand. The gene contains four exons in total. The direct neighbors of TMEM169 include XRCC5 (X-ray repair cross complementing 5) and PECR (peroxisomal trans-2-enoyl-CoA reductase). [1]
Transcription of TMEM169 gene produces five alternatively spliced variants to generate four variants of the transcript. [1] [8] The variants all code for the same protein and have differences within the 5’ UTR region. [1] Variant 1 is the longest transcript (NM_001142310.2) [1] and consists of 3,408 base pairs and four exons.
All four transcripts encode for the same protein (TMEM169) consisting of 297 amino acids. [1] According to SAPS [9] the molecular weight of protein TMEM169 is 33.6 kdal and it has an overall net negative charge (-5.7%). TMEM169 has an isoelectric point of 4.76. [10]
There are two transmembrane domains of Homo sapiens TMEM169 located at amino acids 160-180 and 211-231. [1] The N and C terminus are both located in the cytoplasmic domain. [11] The conceptual translation provides further annotation of Homo sapiens TMEM169 protein.
The specific structure of TMEM169 is unknown, although includes both alpha helices and beta sheets. [12]
The promoter (GXP_6745619) is 1242 base pairs at coordinates 216080866-216082107. [13] It supports 11 coding transcripts.
Promoter | Size | Coordinates | Supporting Transcripts |
---|---|---|---|
GXP_6745619 (+) | 1242 bp | 216080866-216082107 | 11 |
GXP_9516026 (+) | 1040 bp | 216094326-216095365 | Computational |
GXP_9516027 (+) | 1040 bp | 216094696-216095735 | Computational |
GXP_142640 (+) | 1040 bp | 216099253-216100292 | 1 |
Table 2. There are four promoters that result from TMEM169 search on Genomatix. [13]
RNA sequencing data revealed TMEM169 is expressed ubiquitously, although it displays high expression in the brain, particularly during fetal development. [1] HPA RNA-seq normal tissues for TMEM169 were obtained from 95 human tissue samples. The HPA RNA-seq demonstrates highest expression of TMEM169 in the brain (RPKM=3.159). Particularly, in the fetal brain (RPKM= 1.583) and cerebellum(RPKM=0.795). [1]
GEO Profile: GDS3113/220527 [14]
The highest expression of TMEM169 is found in the fetal brain. TMEM169 tends to have a high expression in the brain relative to other tissues, although not to other genes.
The use of polyclonal TMEM169 antibody (NBP2-69796) of a human melanoma cell line (SK-MEL-30) in the host of rabbit demonstrates TMEM169 localization to nucleoplasm, cytosol and centrosome. [15] Strong positivity in glial cells is revealed through immunohistochemical staining of the human cerebral cortex with antibody HPA074877. [16]
The MyHits [17] Tool revealed two types of conserved predicted post-translational modifications.
Predicted Modification | Homo Sapiens Amino Acid Location |
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Casein Kinase 2 phosphorylation sites | 5-8, 47-50, 57-60, 62-65, 123-26, 138-141, 142-145, 269-272, 284-287 |
N-myristoylation site | 226-231, 261-266 |
TMEM169 is well-conserved across strict orthologs shown by the following multiple sequence alignment created Clustal [18] using BoxShade. [19] The multiple sequence alignment of distant orthologs highlighting the transmembrane domains was also created using Clustal [18] and BoxShade. [19] The red boxes illustrate conserved transmembrane domains across orthologs.
Orthologs are found in over 300 organisms within the kingdom metazoan. [1] [8] There are not any orthologs found in fungi or plants. Invertebrates are the most distantly related orthologs, according to BLAST [3] searches. The subset of closely related organisms include mammals, reptiles, birds, and amphibians (E-value 1e-177 to 1e-124). These orthologs range from 78% to 93% sequence similarity to the human protein. Moderately related orthologs to human TMEM169 protein include fish and cephalochordates (similarity= 62%-75%; E-value= 3e-120 to 1e-71). Protein sequences of hemichordates, arthropods, and mollusks are the most distantly related to the human protein sequence (similarity= 56%-64%; E-value= 2e-58 to 1e-44). [3] The most distantly related organism with TMEM169 ortholog is Anopheles albimanus, within the taxonomic group Arthropoda. The size of the gene family for Anopheles albimanus is one and there is only one isoform. [20]
Scientific Name | Common name | Taxonomic group | Accession Number | Date of Divergence (MYA) | % identity |
---|---|---|---|---|---|
Homo sapiens | Human | Mammalia | NP_001135782.1 | 0 | 100 |
Ictidomys tridecemlineatus | Thirteen-lined ground squirrel | Mammalia | XP_005331895.1 | 90 | 90 |
Chelonoidis abingdonii | Pinta island tortoise | Reptilla | XP_032620330 | 312 | 69 |
Pelodiscus sinensis | Chinese softshell turtle | Reptilia | XP_006124795 | 312 | 68 |
Phaethon lepturus | White tailed tropic bird | Aves | XP_010279821.1 | 312 | 67 |
Gallus gallus | Chicken | Aves | XP_015145533.1 | 318 | 66 |
Rhinatrema bivittatum | Two-lined caecilian | Amphibia | XP_029460980.1 | 352 | 66 |
Nanorana parkeri | High himalaya frog | Amphibia | XP_018409958.1 | 353 | 65 |
Danio rerio | Zebrafish | Actinopterygii | NP_001313389.1 | 435 | 50 |
Callorhinchus milii | Australian ghostshark | Chondrichthyes | XP_007908296.1 | 473 | 64 |
Rhincodon typus | Whale shark | Chondrichthyes | XP_020389226.1 | 473 | 60 |
Petromyzon marinus | Sea lamprey | Petrymyzontidae | XP_032801904.1 | 615 | 51 |
Acanthaster planci | Crown of thorns starfish | Echinodermata | XP_022081757.1 | 627 | 40 |
Brachiostoma floridae | Florida lancelet | Cephalochordata | XP_035657488.1 | 684 | 54 |
Saccoglossus kowalevskii | Acorn worm | Hemichordata | XP_002740626 | 684 | 45 |
Drosophila melangogaster | Fruit fly | Arthropoda | NP_650031.1 | 797 | 45 |
Limulus polyphemus | Atlantic horseshoe crab | Arthropoda | XP_022256315 | 797 | 51 |
Octopus vulgaris | Octopus | Mollusca | XP_029635540.1 | 797 | 41 |
Lingula anatina | Lingula anantina | Mollusca | XP_013413871.1 | 797 | 39 |
Anopheles albimanus | Mosquito strain | Arthropoda | XP_035794912.1 | 797 | 38 |
Table 1. Identified orthologs of Homo sapiens TMEM169 protein. The table is organized by increasing DOD (data of divergence from the human lineage) and then by sequence similarity to the human protein (%). The date of divergence was calculated using TimeTree. [21] Seq. is an abbreviation for sequence.
TMEM169 gene first appeared in invertebrates, more specifically in arthropods and mollusks. The approximate date of divergence from humans for arthropods and mollusks is 797 million years ago (MYA). [22] Based upon comparison of the evolution for cytochrome C (a quickly evolving protein) and fibrinogen alpha chain (a slowly evolving protein), TMEM169 gene is evolving at a moderate pace.
RhoU (rho-related GTP-binding protein RhoU) is known to interact with TMEM169 according to PSICQUIC. [23] The pull down assay revealed RhoU as a protein interaction with TMEM169. [24]
A single nucleotide polymorphism of TMEM169, defined as rs3821104, is one of two SNP’s that revealed strong association (p<0.1) with Chronic Obstructive Pulmonary Disease (COPD) within the international COPD genetics network. [25] Additionally, gene TMEM169 is one of the four most down-regulated genes in response to oxidative stress; it is downregulated by 0.50 fold in patients with myocardial infarctions. [26] The gene has association to two different birth defects; neural tube defects and preeclampsia. An amino acid change (p.K41I) in TMEM169 is known to cause neural tube defects [27] and hypermethylated loci cg20968678, associated with TMEM169, leads to early onset preeclampsia. [28]
Transmembrane protein 151B is a protein that in humans is encoded by the TMEM151B gene.
PRR29 is a protein encoded by the PRR29 gene located in humans on chromosome 17 at 17q23.
CRACD-like protein. previously known as KIAA1211L is a protein that in humans is encoded by the CRACDL gene. It is highly expressed in the cerebral cortex of the brain. Furthermore, it is localized to the microtubules and the centrosomes and is subcellularly located in the nucleus. Finally, CRACDL is associated with certain mental disorders and various cancers.
Sperm microtubule associated protein 1 is a protein which in humans is encoded by the SPMAP1 gene. The protein is derived from Homo sapiens chromosome 17. The C17orf98 gene consists of a 6,302 base sequence. Its mRNA has three exons and no alternative splice sites. The protein has 154 amino acids, with no abnormal amino acid levels. C17orf98 has a domain of unknown function (DUF4542) and is 17.6kDa in weight. C17orf98 does not belong to any other families nor does it have any isoforms. The protein has orthologs with high percent similarity in mammals and reptiles. The protein has additional distantly related orthologs across the metazoan kingdom, culminating with the sponge family.
C17orf53 is a gene in humans that encodes a protein known as C17orf53, uncharacterized protein C17orf53. It has been shown to target the nucleus, with minor localization in the cytoplasm. Based on current findings C17orf53 is predicted to perform functions of transport, however further research into the protein could provide more specific evidence regarding its function.
Chromosome 16 open reading frame 46 is a protein of yet to be determined function in Homo sapiens. It is encoded by the C16orf46 gene with NCBI accession number of NM_001100873. It is a protein-coding gene with an overlapping locus.
FAM71E1, also known as Family With Sequence Similarity 71 Member E1, is a protein that in humans is encoded by the FAM71E1 gene. It is thought to be ubiquitously expressed at low levels throughout the body, and it is conserved in vertebrates, particularly mammals and some reptiles. The protein is localized to the nucleus and can be exported to the cytoplasm.
TMEM44 is a protein that in humans is encoded by the TMEM44 gene. DKFZp686O18124 is a synonym of TMEM44.
Uncharacterized protein C16orf86 is a protein in humans that is encoded by the C16orf86 gene. It is mostly made of alpha helices and it is expressed in the testes, but also in other tissues such as the kidney, colon, brain, fat, spleen, and liver. For the function of C16orf86, it is not well understood, however it could be a transcription factor in the nucleus that regulates G0/G1 in the cell cycle for tissues such as the kidney, brain, and skeletal muscles as mentioned in the DNA microarray data below in the gene level regulation section.
FAM71E2, also known as Family With Sequence Similarity 71 Member E2, is a protein that, in humans, is encoded by the FAM71E2 gene. Aliases include C19orf16, Protein FAM71E2, Chromosome 19 open reading frame 16, and Putative Protein FAM71E2. The gene is primarily conserved in mammals, but it is also conserved in two reptile species.
Chromosome 1 open reading frame (C1orf167) is a protein which in humans is encoded by the C1orf167 gene. The NCBI accession number is NP_001010881. The protein is 1468 amino acids in length with a molecular weight of 162.42 kDa. The mRNA sequence was found to be 4689 base pairs in length.
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.
C20orf202 is a protein that in humans is encoded by the C20orf202 gene. In humans, this gene encodes for a nuclear protein that is primarily expressed in the lung and placenta.
Leucine rich single-pass membrane protein 2 is a single-pass membrane protein rich in leucine, that in humans is encoded by the LSMEM2 gene. The LSMEM2 protein is conserved in mammals, birds, and reptiles. In humans, LSMEM2 is found to be highly expressed in the heart, skeletal muscle and tongue.
TMEM275 is a protein that in humans is encoded by the TMEM275 gene. TMEM275 has two, highly-conserved, helical trans-membrane regions. It is predicted to reside within the plasma membrane or the endoplasmic reticulum's membrane.
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