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Draft:Transmembrane protein 145

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Transmembrane protein 145 is a protein, which in humans, is encoded by the TMEM145 gene.[1] TMEM145 has been associated with tumor suppression in breast cancer and prostate cancer.[2][3]

Gene

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TMEM145 (top) vs. Myoglobin (bottom) in situ hybridization using Mus musculus. The mouse was 8 weeks old. Myoglobin does not localize to the brain, so this shows the significance of TMEM145 localization to the brain.

The TMEM145 Gene is located on the plus strand of Chromosome 19 at 19q13.2. This gene spans 11,756 nucleotides and contains 15 exons.[1][4] RNA-sequencing data from NCBI displayed that TMEM145 displays highest expression in the brain with notable expression also in the adrenal glands.[5] Microarray-assessed tissue expression revealed that human TMEM145 is expressed ubiquitously with moderate variation across different tissues.[6] The human TMEM145 protein has a lower than average expression level in comparison to other human proteins.[7] The Human Protein Atlas showed human TMEM145 to have highest expression in the cerebellum with second highest expression in the cerebral cortex.[8] In situ hybridization data from Allen Brain Atlas showed TMEM145 RNA expression in Mus Musculus with highest expression in the cerebellum and dentate gyrus.[9]

TMEM145 gene. The 15 exons are shown in blue and the grey lines are the introns.

Transcript

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Based on NCBI Gene, the longest high-quality mRNA sequence is transcript variant 1 (NM_001366910.1) which encodes isoform 1, the longest protein isoform. This mRNA sequence contains 2298 base pairs.[10]

Protein

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Isoforms of Human TMEM145 protein. "Ex" stands for exon. Red indicates a missing part while blue indicates present exons/parts of exons.

The TMEM145 gene encodes transmembrane protein 145 isoform 1 precursor (NP_001353839.1) with a molecular weight of ~ 60kDa and contains 563 amino acids.[11] The isoelectric point of this protein is 8.8.[12][13][14] There are five protein isoforms and all are displayed in the table.

TMEM145 predicted tertiary structure. Alpha-helices are shown in red while beta-sheets are shown in green. This was created with AlphaFold[15][16] and icn3d.
TMEM145 conceptual translation. This includes the signal peptide, cleavage site, exon boundaries, transmembrane domains, and the start and stop codons.[17][18]
Isoform Accession Number Protein (aa) Molecular Weight (kDa)
Isoform 1 NP_001353839 563 ~60
Isoform 2 NP_775904 493 ~52
Isoform X1 XP_054176598 549 ~60
Isoform X2 XP_054176599 389 ~45
Isoform X3 XP_054176600 375 ~43

Table 1. These are the five protein isoforms of TMEM145.

Transmembrane protein 145 isoform 1 is rich in phenylalanine and tyrosine.[19] The subcellular localization of the human TMEM145 protein is the plasma membrane and cytoskeleton.[4] This protein has a signal peptide from amino acid 1-29 and a cleavage site between amino acid 29 and 30.[20] TMEM145 contains a GOLD domain (Golgi dynamics) and a seven-transmembrane domain.[21] The transmembrane domain is a Rhodopsin-like GPCR Transmembrane Domain.[11]

Evolution/Homology

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Paralog

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TMEM145 is paralogous to integral membrane protein GPR180 (G-protein coupled receptor).[22] GPR180 is produced in vascular smooth muscle cells.[22]

TMEM145 evolution rate. Protein divergence over time for TMEM145 and its paralog, GPR180 compared to Cytochrome C and Fibrinogen Alpha. TMEM145 mutates more slowly than Fibrinogen Alpha but more quickly than Cytochrome C. TMEM145 has a higher rate of sequence divergence than GPR180. The data points for Cytochrome C, Fibrinogen Alpha, and GPR180 are based on different orthologs including Homo sapiens, Mus musculus, Phascolarctos cinereus, Eleutherodactylus coqui, and Danio rerio. GPR180 also included Cuculus canorus. All data points for TMEM145 come from orthologs listed in Table 2.

Orthologs

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Homo sapiens TMEM145 gene orthologs are found in mammals, birds, reptiles, amphibians, fish, and invertebrates.[23] Table 2 displays some orthologs of TMEM145.

TMEM145 unrooted phylogenetic tree. This is an inexhaustive tree. The circles group organisms according to taxonomy.
Genus and Species Common Name Taxonomic Group Date of Divergence From the Human Lineage (*MYA) Accession Number Sequence Length Sequence Identity to Human Protein (%) Sequence Similarity to Human Protein (%)
Homo sapiens Humans Primate 0 NP_001353839 563 100 100
Microcebus murinus Grey Mouse Lemur Primate 74 XP_012613964.1 596 92.45 93.1
Mus musculus House Mouse Rodentia 87 NP_001390132.1 563 96.63 97.2
Rhinolophus ferrumequinum Greater Horseshoe Bat Chiroptera 94 XP_032985445.1 563 97.16 98.4
Phascolarctos cinereus Koala Diprotodontia 160 XP_020858946.1 573 92 76.9
Dermochelys coriacea Leatherback Sea Turtle Testudines 319 XP_038239097 545 77.86 80.6
Cuculus canorus Common Cuckoo Cuculiformes 319 XP_053908563.1 557 70.76 77.1
Python bivittatus Burmese Python Squamata 319 XP_007430515.2 591 76.65 75.7
Apteryx mantelli North Island Brown Kiwi Apterygiformes 319 XP_067172958.1 563 81.17 83
Rhinatrema bivittatum Two-lined Caecilian Gymnophiona 352 XP_029432757.1 546 77.84 81.3
Eleutherodactylus coqui Puerto Rican Coqui Anura 352 XM_066607125.1 547 75.09 79.3
Bufotes viridis European Green Toad Anura 352 CAK8626328.1 547 74.53 77.9
Protopterus annectens West African Lungfish Ceratodontiformes 408 XP_043936719.1 588 80.82 72.6
Danio rerio Zebrafish Cypriniformes 429 XP_686062.6 579 68.72 71.6
Amphiprion ocellaris Clown Anemonefish Perciformes 429 XP_023119489.1 551 67.75 73.7
Hypanus sabinus Atlantic Stingray Myliobatiformes 462 XP_059824187.1 534 65.48 67.7
Branchiostoma floridae Florida Lancelet Amphioxiformes 581 XP_035675017.1 550 54.53 59.1
Acanthaster planci Crown-of-thorns Starfish Valvatida 619 XP_022093045.1 584 47.73 58.5
Saccostrea echinata Blacklip Rock Oyster Ostreida 686 XP_061193107.1 567 42.22 55.8
Oscarella lobularis Sea Sponge Homosclerophorida 758 XP_065845639.1 523 37.29 55.5

Table 2. Incomplete list of orthologs of human TMEM145 (*MYA = millions of years ago).

Clinical Significance

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An African ancestry-specific allele (rs10423769_A) is a genetic variant affecting alternative splicing for the TMEM145 gene.[24] A protective interaction between this allele and the APOE ε4 allele lowered the odds for Alzheimer's Disease by 75% in APOE ε4 heterozygous carriers.[24] The TMEM145 isoforms were found to be more expressed in the cerebellum than the frontal cortex, suggesting that TMEM145 plays a more significant role in the cerebellum. In studying the bone metastasis-derived PC3 prostate cancer cell line, TMEM145 was one of four genes deleted from chromosome 19 in a homozygous deletion.[2] Upon analyzing the DNA methylation pattern, TMEM145 was found to be hypermethylated during stages 1, 2, and 3 of breast cancer, meaning it may be involved in breast cancer control mechanisms.[3] TMEM145 was one of several genes that were highly up-regulated (>10 fold) in both mouse adrenal tumor and human pheochromocytoma.[25]

References

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  1. ^ a b NCBI Gene entry on TMEM145 [1]. Retrieved September 18, 2024.
  2. ^ a b Seim, I., Jeffery, P. L., Thomas, P. B., Nelson, C. C., & Chopin, L. K. (2017). Whole-genome sequence of the metastatic PC3 and LNCaP human prostate cancer cell lines. G3: Genes, Genomes, Genetics, 7(6), 1731-1741. https://academic.oup.com/g3journal/article/7/6/1731/6029848
  3. ^ a b Ivan, J., Patricia, G., & Agustriawan, D. (2021). In silico study of cancer stage-specific DNA methylation pattern in White breast cancer patients based on TCGA dataset. Computational Biology and Chemistry, 92, 107498. https://www.sciencedirect.com/science/article/pii/S1476927121000657?casa_token=DXzlXUnyI6 oAAAAA:GpB5LkB-1tEJKacBJXgNA_MrawhlGeDVVAdnvg84qaOHyilurY_sMe9YDZnkmGQWorPEParX8wM
  4. ^ a b GeneCards TMEM145. (2024, August 6). Retrieved September 20, 2024 from, https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM145.
  5. ^ NCBI Gene entry on TMEM145 [2]
  6. ^ NCBI GEO TMEM145 entry GDS3113 [3]
  7. ^ PaxDB entry on Homo Sapiens TMEM145 [4]
  8. ^ The Human Protein Atlas. [5]
  9. ^ Allen Brain Atlas Entry on TMEM145. [6]
  10. ^ NCBI mRNA entry on TMEM145 Isoform 1 Precursor [7]
  11. ^ a b NCBI Protein entry on TMEM145 [8]
  12. ^ Bjellqvist, B.,Hughes, G.J., Pasquali, Ch., Paquet, N., Ravier, F., Sanchez, J.-Ch., Frutiger, S. & Hochstrasser, D.F. The focusing positions of polypeptides in immobilized pH gradients can be predicted from their amino acid sequences. Electrophoresis 1993, 14, 1023-1031. MEDLINE: 8125050
  13. ^ Bjellqvist, B., Basse, B., Olsen, E. and Celis, J.E. Reference points for comparisons of two-dimensional maps of proteins from different human cell types defined in a pH scale where isoelectric points correlate with polypeptide compositions. Electrophoresis 1994, 15, 529-539. MEDLINE: 8055880
  14. ^ Gasteiger E., Hoogland C., Gattiker A., Duvaud S., Wilkins M.R., Appel R.D., Bairoch A.; Protein Identification and Analysis Tools on the Expasy Server; (In) John M. Walker (ed): The Proteomics Protocols Handbook, Humana Press (2005).
  15. ^ Jumper, J et al. Highly accurate protein structure prediction with AlphaFold. Nature (2021).
  16. ^ Varadi, M et al. AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences. Nucleic Acids Research (2024).
  17. ^ Six-frame translation. Retrieved September 18, 2024, from https://www.bioline.com/media/calculator/01 13.html
  18. ^ TMEM145 isoform precursor 1 (NP 001353839.1)
  19. ^ Madeira F, Madhusoodanan N, Lee J, Eusebi A, Niewielska A, Tivey ARN, Lopez R, Butcher S. (2024) The EMBL-EBI Job Dispatcher sequence analysis tools framework in 2024. Nucleic Acids Research, April 10, 2024; doi: 10.1093/nar/gkae241
  20. ^ DTU Department of Health Technology. SignalP 6.0 Tool. [9]
  21. ^ Hoel, C. M., Zhang, L., & Brohawn, S. G. (2022). Structure of the GOLD-domain seven-transmembrane helix protein family member TMEM87A. eLife, 11, e81704. https://doi.org/10.7554/eLife.81704 Accessed September 20, 2024.
  22. ^ a b NCBI Gene entry on GPR180 [10]
  23. ^ NCBI Gene entry on TMEM145 [11]. Retrieved September 18, 2024.
  24. ^ a b Wang, L., Vasquez, M. L., Nuytemans, K., Rajabli, F., Whitehead, P., Gearing, M., ... & Vance, J. M. (2023). Characterization of an African ancestry‐specific protective allele of the APOE ε4 allele for Alzheimer's disease risk. Alzheimer's & Dementia, 19, e080287. https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.080287
  25. ^ Hattori, Y., Kanamoto, N., Kawano, K., Iwakura, H., Sone, M., Miura, M., ... & Maitani, Y. (2010). Molecular characterization of tumors from a transgenic mouse adrenal tumor model: Comparison with human pheochromocytoma. International journal of oncology, 37(3), 695-705. https://www.spandidos-publications.com/ijo/37/3/695
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