TMEM267 is a protein that in humans is encoded by the TMEM267 gene. It is a possible oncogene which encodes a transmembrane protein. The function of TMEM267 most likely involves transportation of molecules from the cytosol, as the presence of motifs and domains involved in transportation were conserved in orthologs. TMEM267 has orthologs in many species and is expressed at highest levels in the thyroid.
Known aliases for TMEM267include C5orf28, B2RDA6, and Q9H6Z2. [5] TMEM267 is found on chromosome 5, cytoband p12 on the reverse strand between base pairs 43,444,252 and 43,485,178, meaning it has length of 40,927 base pairs. [6] TMEM267 produces 13 distinct gt-ag introns and 12 different mRNAs, with 9 alternatively spliced variants and 3 unspliced forms. It has 2 alternative promoters and 7 validated polyadenylation sites. [7] There are 6 predicted promoters of varying lengths. [8]
| Name | Accession Number | Number of Exons | Size (bp) |
|---|---|---|---|
| Transcript Variant 1 | NM_022483 | 3 | 2736 |
| Transcript Variant 2 | NM_001377394.1 | 4 | 2887 |
| Transcript Variant X2 | XM_011514075 | 4 | 3574 |
| Transcript Variant 3 | NM_001377395.1 | 5 | 3210 |
| Transcript Variant 4 | NM_001377396.1 | 3 | 2960 |
| Transcript Variant 5 | NM_001377397.1 | 4 | 3108 |
| Transcript Variant 6 | NM_001377398.1 | 5 | 3283 |
| Transcript Variant 7 | NM_001377399.1 | 3 | 3377 |
| Transcript Variant 8 | NM_001377400.1 | 4 | 3528 |
| Transcript Variant 9 | NM_001377401.1 | 4 | 2834 |
| Transcript Variant 10 | NM_001377402.1 | 3 | 2809 |
| Transcript Variant 11 | NM_001377403.1 | 5 | 2979 |
The TMEM267 protein in all isoforms is 215 amino acids in length. [9] All of the isoforms have a predicted molecular mass of 24.2 kDa and theoretical isoelectric point of 8.91. [10] [11] There was an above average percentage of histidine and tryptophan residues. The percentage of asparagine, glutamic acid and tyrosine were below average. After analysis of Antarctic Yellowbelly Rockcod, Tropical clawed frog, Willow flycatcher, Common wall lizard, and pacific white-sided dolphin orthologs, above average percent composition of tryptophan and below average percent composition of asparagine and glutamic acid residues was conserved across amphibians, fish, mammals, birds, and reptiles. [12]
| Name | Accession Number | Size (aa) |
|---|---|---|
| Transcript Variant 2 | NP_001364323.1 | 215 |
| Transcript Variant X2 | XM_011514075 | 215 |
| Transcript Variant 3 | NP_001364324 | 215 |
| Transcript Variant 4 | NP_001364325 | 215 |
| Transcript Variant 5 | NP_001364326 | 215 |
| Transcript Variant 6 | NP_001364327 | 215 |
| Transcript Variant 7 | NP_001364328 | 215 |
| Transcript Variant 8 | NP_001364329 | 215 |
| Transcript Variant 9 | NP_001364330 | 215 |
| Transcript Variant 10 | NP_001364331 | 215 |
| Transcript Variant 11 | NP_001364332 | 215 |
| Transcript Variant 12 | NP_071928 | 215 |
The predictions surrounding the transmembrane regions of TMEM267 are unclear. Some prediction tools claim there are no transmembrane or hydrophobic regions. [13] Others predict between 2 and 5 transmembrane domains. [14] [15] The consensus is that there is most likely at least two transmembrane regions in the amino acids in the region around 113-135 and 176–198. The helical wheel diagrams of the three transmembrane regions given by NCBI Gene indicate the presence of polar amino acid which are basic and acidic in the transmembrane regions which is unusual. [16]
Two domains were predicted for TMEM267. First is a LaxA-binding, inner membrane-associated mutative hydrolase, which indicates that TMEM267 may be involved as a group of membrane-bound metal-dependent hydrolases that may act as phospholipases. The other is predicted to be a Vacuolar sorting protein 9 (VPS9) domain, which indicates that TMEM267 may be involved in trafficking of molecules to lysosomes and cell signaling. [17] [18]
| Domain | Location | Conserved in Isoforms | Conserved in Orthologs |
|---|---|---|---|
| LaxA binding site | 55-161 | yes | yes |
| Vacuolar Sorting Protein 9 (VSP9) binding site | 175-199 | yes | no |
Motifs that were predicted are a canonical arginine-containing phosphopeptide motif, which may be involved in the transportation of the 14-3-3 proteins which are involved in many cellular processes. [19] A binding site for Interferon Regulatory Factor 3 (IRF-3) protein may be involved in the signaling pathway which actives IRF-3 in the presence of viral and microbial infections. [20] Tryptophan-based motifs which enable targeting of tethering to a homology domain could mean that TMEM267 may play a role in mediating transportation form the Golgi to the ER. The coatomer subunit delta (delta-COP) is a cytosolic protein complex that binds to motifs and associates with vesicles involved in protein transport from the ER and Golgi. [21] An LC3-Interacting Region (LIR) motif was predicted, which indicates that TMEM267 may be involved in the autophagy pathway, which is involved in transferring of cytoplasmic material in autophagosomes to lysosomes as well as removal of toxic macromolecules and organelles to maintain the health of the cell. [22] The Class 2 PDZ-binding motif predicts that TMEM267 could be involved with PDZ proteins, which are influential in trafficking, recycling, and intracellular sorting. [23] The Wxxx[FY] motif indicates that TMEM267 could be involved in the interaction of Pex14 with Pex5 proteins. [24] [25]
| Motif | Location | Conserved in Isoforms | Conserved in Orthologs | Cellular Location |
|---|---|---|---|---|
| Canonical arginine-containing phosphopeptide motif | 49-56 | Yes | Yes | cytosol |
| Interferon Regulatory Factor 3 (IRF-3) binding site | 139-146 | Yes | Yes | cytosol |
| Tryptophan-based motifs that enable tethering to a homology domain | 144-151 | Yes | Yes | cytosol |
| LIR motif | 64-68 | Yes | Yes | cytosol |
| PDZ-binding motif | 210-215 | Yes | Yes | cytosol |
| Wxxx[FY] motif | 166-170 | Yes | Yes | cytosol |
Overall, TMEM267 is most likely found in the cytoplasm. The TMEM267 protein was claimed to be localized in the nucleoplasm of cells. [26] Another tool predicted it to be found in the cytoplasm (69.6%) and mitochondrial (13%) with reliability 94.1 from Reinhardt's method for Cytoplasmic/Nuclear discrimination. [27] TMEM267 is not abundant in the human body at 0.05 ppm. [28]
Secondary structure predictions were done using the transmembrane regions for TMEM267 given by NCBI Gene. The prediction servers indicate that that amino acids 1-76 are helical in nature. The extracellular and intracellular regions of the TMEM267 protein are predicted to be a combination of alpha helices and beta sheets, but there is not a consensus. [29] [30] [31]
There is no evidence of post-translational modifications of the TMEM267 protein found in tissues. [32] According to protein sequence analysis, there is a prediction of one palmitoylation site, a SUMO Interaction and two sumoylation sites. [33] [34] There are many predicted phosphorylation sites in the non-transmembrane regions with various protein kinases including AGC, CKII, and Case kinase II. [35] [36] One site is predicted to be acetylated in the N-terminus of TMEM267. [37] TMEM267 has four predicted glycation sites, as well as seven O-beta-GlycNAc sites. [38] [39]
TMEM267 protein is expressed in over 100 tissues in the body, meaning it has low tissue specificity, but is largely present in the thyroid, pituitary gland, and pancreas. Data from NCBI Geo shows that there are higher levels of expression in mainly the thyroid but other tissues have varied expression for each sample. There seems to be, on average, highest expression levels in thyroid, ovaries, testes, pituitary gland, and pancreas. TMEM267 is not expressed at a very high level compared to Beta Actin, which has almost triple the RPKM compared to TMEM267. [40] TMEM267 is expressed at 1.6 times the average gene on chromosome 5. [41]
The table below describes a curated set of transcription factors which are predicted to bind in the Genomatix predicted TMEM267 promoter region. [42]
| Transcription Factor | Detailed information |
|---|---|
| RU49 | Zinc finger proliferation 1-Zipro |
| SORY | SOX-SOY-sex/testis determining and related HMG box factors |
| FKHD | Fork head domain factors |
| BRAC | Brachyury gene, mesoderm developmental factor |
| EVI1 | EVI1-myleoid transformation protein |
| VTBP | Vertebrate TATA binding protein factor |
| RUSH | SWI/SNF related nucelophosphoproteins with RING finger DNA binding motif |
| NKXH | NKX homeodomain factors |
| BRN5 | Brn-5 POU domains |
| PDX1 | Pancreatic and intestinal homeodomain TF |
| CEBPA/B | CCAAT/Enhancer Binding Protein |
| CAAT | CCAAT binding factors |
| SPZ1 | Testis-specific bHLH-Zip TFs |
| NFAT | Nuclear factor of activated T-cells |
| DMRT | DM- domain-containing TFs |
| ZF01 | C2H2 zinc finger TF1 |
| CREB | cAMP-responsive element binding proteins |
| XBBF | X-box binding factors |
| GCNR | Germ cell nuclear receptor |
| PLZF | C2H2 zinc finger protein PLZF |
TMEM267 was predicted to interact with the proteins in the table below.
| Protein Name | UniProt Label | Function | Location |
|---|---|---|---|
| TMEM52B | Q4KMG9 | Function has not been studied | Integral component of membrane, extracellular region |
| TMEM14B | Q9NUH8 | Involved in the cortical expansion and folding in the developing neocortex; may drive neural progenitor proliferation through nuclear translocation | Integral component of membrane |
| RTP2 (Receptor-transporting protein 2) | Q5QGT7 | Promotes functional cell surface expression of olfactory receptor | Plasma membrane |
| SAR1A | Q9NR31 | Involved in transport from the ER to the Golgi apparatus; SAR1S-GTP-dependent assembly of SEC16A on the ER membrane form an organized scaffold defining ER exit sites | ER, Golgi apparatus |
| STX7 (Syntaxin-7) | Q15400 | May be involved in protein trafficking from the plasma membrane to early endosome; mediates trafficking from early to late endosomes and lysosomes | Endosome, plasma membrane |
| CPLX4 (Complexin-4) | Q7Z7G2 | Regulates SNARE protein complex-mediated synaptic vesicle fusion | Plasma membrane |
| APP (Amyloid-beta precursor protein P4) | P05067 | Functions as cell surface receptor in neurons; involved in cell mobility and transcription regulation | Extracellular region/secreted, plasma membrane, endosome, nucleus, cytoplasmic vesicle |
| EGFR | P00533 | Ligand binding trigger receptor homo/heterodimerization and autophosphorylation on key cytoplasmic residues; this phosphorylated receptor recruits adaptor proteins which activate downstream signaling cascades | Nuclear membrane, ER membrane |
| LNPEP (Leucyl-cystinyl aminopeptidase) | Q9UIQ6 | Release of an N-terminal amino acid, cleaves before cysteine and leucine; helps maintain homeostasis during pregnancy | Plasma membrane, extracellular region |
| ECM29 | Q5VYK3 | Adaptor/scaffolding protein which binds to specific proteins; may couple the proteasome to ER, endosome, and centrosome | Nucleus, centrosome, ER, endosome, cytoplasmic vesicle |
TMEM267 has orthologs in Mammalia, Reptilia, Amphibia, Mollusca, Arthropoda, Branchiostoma, Trichoplax, Oomycetes, and Bacteria, among others, but has no paralogs. A table of select orthologs is listed below. [43]
| Genus and Species | Common Name | Taxonomic Group | Estimated Date of Divergence (MYA) | Accession Number | Sequence Length (aa) | Sequence Alignment | Sequence Similarity |
|---|---|---|---|---|---|---|---|
| Nannospalax galili | Northern Israeli Blind Subterranean Mole | Rodentia | 90 | XP_008831143.1 | 215 | 85.19% | 93% |
| Opisthocomus hoazin | Reptile Bird | Opisthocomiformes | 312 | XP_009941974.1 | 215 | 83.26% | 92% |
| Protobothrops mucrosquamatus | Venomous pit viper | Squamata | 312 | XP_015672610.1 | 219 | 82.16% | 89% |
| Xenopus Tropicalis | Tropical clawed frog | Anura | 351.8 | XP_031750178.1 | 215 | 74.88% | 86% |
| Notothenia coriiceps | Antarctic Yellowbelly Rockcod | Perciformes | 435 | XP_010772860.1 | 244 | 67.21% | 82% |
| Branchiostoma belcheri | Branchiostoma | Amphioxiformes | 684 | XP_019622820.1 | 215 | 32.09% | 63% |
| Strongylocentrotus purpuratus | Purple Sea Urchin | Echinodermata | 684 | XP_030828106.1 | 221 | 36.3% | 59% |
| Aethina tumida | Small Hive Beetle | Coleoptera | 797 | XP_019869992.1 | 201 | 35.82% | 49% |
| Crassostrea gigas | Pacific Oyster | Ostreoida | 797 | XP_011423125.1 | 209 | 34.93% | 52% |
TMEM267 is predicted to evolve slower than Fibrinogen Alpha Chain but faster than Cytochrome C. [44]
The protein was identified as a member of a large group of proteins that comprise a filter in mammalian cells which allow selective passage of proteins in and out of the cilium, regulating the contents. [45] TMEM267 was one of ten genes selected using the two-sample t-test and Wilcoxon Mann-Whitney analysis of training data on atopic dermatitis (a skin disease characterized by areas of severe itching, redness, scaling, and loss of the surface of the skin), as a gene that provided the most information about the separation between the control and experimental groups. [46] TMEM267 is mentioned in articles pertaining to the down-regulation of two miRNAs, one of which is involved in regulating a wide variety of cellular functions, such as proliferation, apoptosis, migration, and differentiation, all of which are vital for the normal development of heart cells. [47] [48]
TMEM267 protein was shown to be mutated in 0.1-0.9% of colorectal, stomach, lung, endometrial, kidney, and breast cancer. [49] TMEM267 was affected by increased levels of the NUDT21 gene, and was identified as a part of a large group of possible oncogenes, that when the 3'-UTR is shortened, can cause uncontrollable cell growth. [50] It is a part of a group of genes which can possibly identify survival rates of patients with PNI+ tongue cancer. [51] TMEM267 was shown to be one of 26 over-expressed genes on chromosome 5p, meaning it belongs to a group of genes which likely provides cancer cells with advantages in growth and invasion of surrounding cells. [52] In addition, researchers from The Johns Hopkins University filed a patent for 63 genes, including TMEM267 which had increased expression in the presence of HMGA1 protein compared to the control group, which they think could be of use in a method of inhibiting cancer stem cells with HMGA1 inhibitors. [53]
Transmembrane protein 63A is a protein that in humans is encoded by the TMEM63A gene. The mature human protein is approximately 92.1 kilodaltons (kDa), with a relatively high conservation of mass in orthologs. The protein contains eleven transmembrane domains and is inserted into the membrane of the lysosome. BioGPS analysis for TMEM63A in humans shows that the gene is ubiquitously expressed, with the highest levels of expression found in T-cells and dendritic cells.
Transmembrane protein 242 (TMEM242) is a protein that in humans is encoded by the TMEM242 gene. The tmem242 gene is located on chromosome 6, on the long arm, in band 2 section 5.3. This protein is also commonly called C6orf35, BM033, and UPF0463 Transmembrane Protein C6orf35. The tmem242 gene is 35,238 base pairs long, and the protein is 141 amino acids in length. The tmem242 gene contains 4 exons. The function of this protein is not well understood by the scientific community. This protein contains a DUF1358 domain.
Transmembrane protein 131 (TMEM131) is a protein that is encoded by the TMEM131 gene in humans. The TMEM131 protein contains three domains of unknown function 3651 (DUF3651) and two transmembrane domains. This protein has been implicated as having a role in T cell function and development. TMEM131 also resides in a locus (2q11.1) that is associated with Nievergelt's Syndrome when deleted.
TMEM143 is a protein that in humans is encoded by TMEM143 gene. TMEM143, a dual-pass protein, is predicted to reside in the mitochondria and high expression has been found in both human skeletal muscle and the heart. Interaction with other proteins indicate that TMEM143 could potentially play a role in tumor suppression/expression and cancer regulation.
Transmembrane protein 251, also known as C14orf109 or UPF0694, is a protein that in humans is encoded by the TMEM251 gene. One notable feature of this protein is the presence of proline residues on one of its predicted transmembrane domains., which is a determinant of the intramitochondrial sorting of inner membrane proteins.
Transmembrane protein 261 is a protein that in humans is encoded by the TMEM261 gene located on chromosome 9. TMEM261 is also known as C9ORF123 and DMAC1, Chromosome 9 Open Reading Frame 123 and Transmembrane Protein C9orf123 and Distal membrane-arm assembly complex protein 1.
Transmembrane protein 268 is a protein that in humans is encoded by TMEM268 gene. The protein is a transmembrane protein of 342 amino acids long with eight alternative splice variants. The protein has been identified in organisms from the common fruit fly to primates. To date, there has been no protein expression found in organisms simpler than insects.
Transmembrane protein 255A is a protein that is encoded by the TMEM255A gene. TMEM255A is often referred to as family with sequence similarity 70, member A (FAM70A). The TMEM255A protein is transmembrane and is predicted to be located the nuclear envelope of eukaryote organisms.
Transmembrane Protein 217 is a protein encoded by the gene TMEM217. TMEM217 has been found to have expression correlated with the lymphatic system and endothelial tissues and has been predicted to have a function linked to the cytoskeleton.
Transmembrane protein 254 is a transmembrane protein that is encoded by the TMEM254 gene, it is predicted to have many orthologs across eukaryotes.
Transmembrane protein 171 (TMEM171) is a protein that in humans is encoded by the TMEM171 gene.
Transmembrane protein 125 is a protein that, in humans, is encoded by the TMEM125 gene. It has 4 transmembrane domains and is expressed in the lungs, thyroid, pancreas, intestines, spinal cord, and brain. Though its function is currently poorly understood by the scientific community, research indicates it may be involved in colorectal and lung cancer networks. Additionally, it was identified as a cell adhesion molecule in oligodendrocytes, suggesting it may play a role in neuron myelination.
Transmembrane protein 179 is a protein that in humans is encoded by the TMEM179 gene. The function of transmembrane protein 179 is not yet well understood, but it is believed to have a function in the nervous system.
C22orf23 is a protein which in humans is encoded by the C22orf23 gene. Its predicted secondary structure consists of alpha helices and disordered/coil regions. It is expressed in many tissues and highest in the testes and it is conserved across many orthologs.
Transmembrane protein 221 (TMEM221) is a protein that in humans is encoded by the TMEM221 gene. The function of TMEM221 is currently not well understood.
Family with Sequence Similarity 155 Member B is a protein in humans that is encoded by the FAM155B gene. It belongs to a family of proteins whose function is not yet well understood by the scientific community. It is a transmembrane protein that is highly expressed in the heart, thyroid, and brain.
Transmembrane protein 247 is a multi-pass transmembrane protein of unknown function found in Homo sapiens encoded by the TMEM247 gene. Notable in the protein are two transmembrane regions near the c-terminus of the translated polypeptide. Transmembrane protein 247 has been found to be expressed almost entirely in the testes.
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.
Transmembrane protein 39B (TMEM39B) is a protein that in humans is encoded by the gene TMEM39B. TMEM39B is a multi-pass membrane protein with eight transmembrane domains. The protein localizes to the plasma membrane and vesicles. The precise function of TMEM39B is not yet well-understood by the scientific community, but differential expression is associated with survival of B cell lymphoma, and knockdown of TMEM39B is associated with decreased autophagy in cells infected with the Sindbis virus. Furthermore, the TMEM39B protein been found to interact with the SARS-CoV-2 ORF9C protein. TMEM39B is expressed at moderate levels in most tissues, with higher expression in the testis, placenta, white blood cells, adrenal gland, thymus, and fetal brain.
Transmembrane protein 101 (TMEM101) is a protein that in humans is encoded by the TMEM101 gene. The TMEM101 protein has been demonstrated to activate the NF-κB signaling pathway. High levels of expression of TMEM101 have been linked to breast cancer.
