TMEM267

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.

PHYRE Tertiary Structure prediction for TMEM267
TMEM267
Identifiers
AliasesTMEM267, C5orf28, transmembrane protein 267
External IDsMGI: 3648543 HomoloGene: 49708 GeneCards: TMEM267
Gene location (Human)
Chr.Chromosome 5 (human)[1]
Band5p12Start43,444,252 bp[1]
End43,483,893 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

64417

633640

Ensembl

ENSG00000151881

ENSMUSG00000074634

UniProt

Q0VDI3

Q8VDR5

RefSeq (mRNA)

NM_022483

NM_001039244
NM_001177666
NM_001370626
NM_001370627

RefSeq (protein)

NP_001034333
NP_001171137
NP_001357555
NP_001357556

Location (UCSC)Chr 5: 43.44 – 43.48 MbChr 13: 119.49 – 119.61 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

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]

TMEM267 location on chromosome 5 in humans from GeneCards.
NameAccession NumberNumber of ExonsSize (bp)
Transcript Variant 1NM_02248332736
Transcript Variant 2NM_001377394.142887
Transcript Variant X2XM_01151407543574
Transcript Variant 3NM_001377395.153210
Transcript Variant 4NM_001377396.132960
Transcript Variant 5NM_001377397.143108
Transcript Variant 6NM_001377398.153283
Transcript Variant 7NM_001377399.133377
Transcript Variant 8NM_001377400.143528
Transcript Variant 9NM_001377401.142834
Transcript Variant 10NM_001377402.132809
Transcript Variant 11NM_001377403.152979

Protein

General information

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]

Isoforms
NameAccession NumberSize (aa)
Transcript Variant 2NP_001364323.1215
Transcript Variant X2XM_011514075215
Transcript Variant 3NP_001364324215
Transcript Variant 4NP_001364325215
Transcript Variant 5NP_001364326215
Transcript Variant 6NP_001364327215
Transcript Variant 7NP_001364328215
Transcript Variant 8NP_001364329215
Transcript Variant 9NP_001364330215
Transcript Variant 10NP_001364331215
Transcript Variant 11NP_001364332215
Transcript Variant 12NP_071928215

Transmembrane regions

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]

NetWheels Prediction for TMEM267 transmembrane regions
Protter schematic of transmembrane regions of TMEM267 in humans.

Domains

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]

DomainLocationConserved in IsoformsConserved in Orthologs
LaxA binding site55-161yesyes
Vacuolar Sorting Protein 9 (VSP9) binding site175-199yesno

Motifs

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]

MotifLocationConserved in IsoformsConserved in OrthologsCellular Location
Canonical arginine-containing phosphopeptide motif49-56YesYescytosol
Interferon Regulatory Factor 3 (IRF-3) binding site139-146YesYescytosol
Tryptophan-based motifs that enable tethering to a homology domain144-151YesYescytosol
LIR motif64-68YesYescytosol
PDZ-binding motif210-215YesYescytosol
Wxxx[FY] motif166-170YesYescytosol

Localization and abundance
TMEM267 protein abundance in the human body from PAXdb

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

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]

PHYRE2 prediction of secondary and tertiary structure for TMEM267

Post-translational modifications

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]

Expression

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]

Expression data for TMEM267 in specific tissues.

Interactions

Transcription factors

The table below describes a curated set of transcription factors which are predicted to bind in the Genomatix predicted TMEM267 promoter region.[42]

Transcription FactorDetailed information
RU49Zinc finger proliferation 1-Zipro
SORYSOX-SOY-sex/testis determining and related HMG box factors
FKHDFork head domain factors
BRACBrachyury gene, mesoderm developmental factor
EVI1EVI1-myleoid transformation protein
VTBPVertebrate TATA binding protein factor
RUSHSWI/SNF related nucelophosphoproteins with RING finger DNA binding motif
NKXHNKX homeodomain factors
BRN5Brn-5 POU domains
PDX1Pancreatic and intestinal homeodomain TF
CEBPA/BCCAAT/Enhancer Binding Protein
CAATCCAAT binding factors
SPZ1Testis-specific bHLH-Zip TFs
NFATNuclear factor of activated T-cells
DMRTDM- domain-containing TFs
ZF01C2H2 zinc finger TF1
CREBcAMP-responsive element binding proteins
XBBFX-box binding factors
GCNRGerm cell nuclear receptor
PLZFC2H2 zinc finger protein PLZF

Interacting proteins

TMEM267 was predicted to interact with the proteins in the table below.

Protein NameUniProt LabelFunctionLocation
 TMEM52BQ4KMG9Function has not been studiedIntegral component of membrane, extracellular region
TMEM14BQ9NUH8Involved in the cortical expansion and folding in the developing neocortex; may drive neural progenitor proliferation through nuclear translocationIntegral component of membrane
RTP2 (Receptor-transporting protein 2)Q5QGT7Promotes functional cell surface expression of olfactory receptorPlasma membrane
SAR1AQ9NR31Involved 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 sitesER, Golgi apparatus
STX7 (Syntaxin-7)Q15400May be involved in protein trafficking from the plasma membrane to early endosome; mediates trafficking from early to late endosomes and lysosomesEndosome, plasma membrane
CPLX4 (Complexin-4)Q7Z7G2Regulates SNARE protein complex-mediated synaptic vesicle fusionPlasma membrane
APP (Amyloid-beta precursor protein P4)P05067Functions as cell surface receptor in neurons; involved in cell mobility and transcription regulationExtracellular region/secreted, plasma membrane, endosome, nucleus, cytoplasmic vesicle
EGFRP00533Ligand binding trigger receptor homo/heterodimerization and autophosphorylation on key cytoplasmic residues; this phosphorylated receptor recruits adaptor proteins which activate downstream signaling cascadesNuclear membrane, ER membrane
LNPEP (Leucyl-cystinyl aminopeptidase)Q9UIQ6Release of an N-terminal amino acid, cleaves before cysteine and leucine; helps maintain homeostasis during pregnancyPlasma membrane, extracellular region
ECM29Q5VYK3Adaptor/scaffolding protein which binds to specific proteins; may couple the proteasome to ER, endosome, and centrosomeNucleus, centrosome, ER, endosome, cytoplasmic vesicle

Homology and evolution

Orthologs and paralogs

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 SpeciesCommon NameTaxonomic GroupEstimated Date of Divergence (MYA)Accession NumberSequence Length (aa)Sequence AlignmentSequence Similarity
Nannospalax galiliNorthern Israeli Blind Subterranean MoleRodentia90XP_008831143.121585.19%93%
Opisthocomus hoazinReptile BirdOpisthocomiformes312XP_009941974.121583.26%92%
Protobothrops mucrosquamatusVenomous pit viperSquamata312XP_015672610.121982.16%89%
Xenopus TropicalisTropical clawed frogAnura351.8XP_031750178.121574.88%86%
Notothenia coriicepsAntarctic Yellowbelly RockcodPerciformes435XP_010772860.124467.21%82%
Branchiostoma belcheriBranchiostomaAmphioxiformes684XP_019622820.121532.09%63%
Strongylocentrotus purpuratusPurple Sea UrchinEchinodermata684XP_030828106.122136.3%59%
Aethina tumidaSmall Hive BeetleColeoptera 797XP_019869992.120135.82%49%
Crassostrea gigasPacific OysterOstreoida797XP_011423125.120934.93%52%

Evolution

TMEM267 is predicted to evolve slower than Fibrinogen Alpha Chain but faster than Cytochrome C.[44]

TMEM267 Evolutionary Graph

Function

Clinical significance

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]

Cancer

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]

References
  1. GRCh38: Ensembl release 89: ENSG00000151881 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000074634 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. GeneCards.org entry on TMEM267
  6. GeneCards.org entry on TMEM267
  7. UniProtKB entry on Q0VDI3 (TM267_HUMAN)
  8. El Dorado at Genomatix
  9. NCBI (National Center for Biotechnology Information) AceView entry on C5orf28
  10. GeneCards.org entry on TMEM267
  11. ExPASy Compute pI/MW predictor /
  12. SAPS entry on TMEM267
  13. SAPS entry on TMEM267
  14. ELM entry for TMEM267
  15. Prodom entry on TMEM267
  16. NetWheels Helical Projection for TMEM267
  17. MotifFinder entry on TMEM267
  18. Hislop JN, Marley A, von Zastrow M. Role of Mammalian Vacuolar Protein-sorting Proteins in Endocytic Trafficking of a Non-ubiquitinated G Protein-coupled Receptor to Lysosomes. J Biol Chem 2004;279:22522–22531.
  19. ELM Detail of Canonical Arginine-containing phosphopeptide motif
  20. IRF3 information
  21. delta-COP protein
  22. Wirth, M., Zhang, W., Razi, M. et al. Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins. Nat Commun 10, 2055 (2019).
  23. Romero, G., von Zastrow, M., & Friedman, P. A. (2011). Role of PDZ proteins in regulating trafficking, signaling, and function of GPCRs: means, motif, and opportunity. Advances in pharmacology (San Diego, Calif.), 62, 279–314.
  24. ELM Details for LIG_Pex14
  25. ELM entry for TMEM267
  26. The Human Protein Atlas entry on TMEM267
  27. PSORT prediction for TMEM267
  28. PaxDb protein abundance
  29. Chau-Fasman prediction for TMEM267
  30. GOR4 prediction for TMEM267
  31. Phyre 2 Prediction for TMEM267
  32. The Human Protein Atlas entry on TMEM267
  33. CSS-Palm for TMEM267
  34. SUMOsp prediction for TMEM267
  35. GPS for TMEM267
  36. NetPhos prediction for TMEM267
  37. NetACET prediction for TMEM267
  38. NetGlycate prediction for TMEM267
  39. YinOYang prediction for TMEM267
  40. NCBI (National Center for Biotechnology Information) AceView entry on C5orf28
  41. NCBI (National Center for Biotechnology Information) AceView entry on C5orf28
  42. El Dorado at GenoMatix MatInspector for TMEM267
  43. NCBI (National Center for Biotechnology Information) AceView entry on C5orf28
  44. TimeTree Data on Date of Divergence
  45. Valentine, Megan Smith, "Polycystin-2 (PKD2), Eccentric (XNTA), and Meckelin (MKS3) in the Ciliated Model Organism Paramecium tetraurelia" (2015). Graduate College Dissertations and Theses. 419.
  46. Tadesse, Dawit. (2018). A Comparison of Selected Parametric and Non-Parametric Statistical Approaches for Candidate Genes Selection in Transcriptome Data.
  47. Han, S., Wang, W., Duan, L., Hou, Z., Zeng, J., Li, L., … Jiang, L. (2019). MicroRNA profiling of patients with sporadic atrial septal defect. Biotechnology & Biotechnological Equipment, 33(1), 510–519.
  48. Sun, Xiaoyan & Song, Zhenhua & Si, Yawei & Wang, Jin-Hui. (2018). microRNA and mRNA profiles in ventral tegmental area relevant to stress-induced depression and resilience. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 86. 10.1016
  49. Yao, Z., Darowski, K., St-Denis, N., Wong, V., Offensperger, F., Villedieu, A., … Stagljar, I. (2017). A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome. Molecular cell, 65(2), 347–360.
  50. Xiong, M., Chen, L., Zhou, L., Ding, Y., Kazobinka, G., Chen, Z., & Hou, T. (2019). NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation. Theranostics, 9(24), 7156–7167.
  51. Reddy RB, Khora SS, Suresh A (2019) Molecular prognosticators in clinically and pathologically distinct cohorts of head and neck squamous cell carcinoma—A meta-analysis approach. PLoS ONE 14(7): e0218989.
  52. Scotto, L., Narayan, G., Nandula, S.V. et al. Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha. Mol Cancer 7, 58 (2008).
  53. Google Patents
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