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.[5][8] RNA-sequencing data from NCBI displayed that TMEM145 displays highest expression in the brain with notable expression also in the adrenal glands.[9] Microarray-assessed tissue expression revealed that human TMEM145 is expressed ubiquitously with moderate variation across different tissues.[10] The human TMEM145 protein has a lower than average expression level in comparison to other human proteins.[11] The Human Protein Atlas showed human TMEM145 to have highest expression in the cerebellum with second highest expression in the cerebral cortex.[12] In situ hybridization data from Allen Brain Atlas showed TMEM145 RNA expression in Mus Musculus with highest expression in the cerebellum and dentate gyrus.[13]
TMEM145 gene. The 15 exons are shown in blue and the grey lines are the introns.
Transcript
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.[14]
Protein
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.[15] The isoelectric point of this protein is 8.8.[16][17][18] 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[19][20] and icn3d.TMEM145 conceptual translation. This includes the signal peptide, cleavage site, exon boundaries, transmembrane domains, and the start and stop codons.[21][22]
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.[23] The subcellular localization of the human TMEM145 protein is the plasma membrane and cytoskeleton.[8] This protein has a signal peptide from amino acid 1-29 and a cleavage site between amino acid 29 and 30.[24] TMEM145 contains a GOLD domain (Golgi dynamics) and a seven-transmembrane domain.[25] The transmembrane domain is a Rhodopsin-like GPCR Transmembrane Domain.[15]
Evolution/Homology
Paralog
TMEM145 is paralogous to integral membrane protein GPR180 (G-protein coupled receptor).[26] GPR180 is produced in vascular smooth muscle cells.[26]
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.
Table 2. Incomplete list of orthologs of human TMEM145 (*MYA = millions of years ago).
Clinical Significance
An African ancestry-specific allele (rs10423769_A) is a genetic variant affecting alternative splicing for the TMEM145 gene.[28] 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.[28] 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.[6] 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.[7] TMEM145 was one of several genes that were highly up-regulated (>10 fold) in both mouse adrenal tumor and human pheochromocytoma.[29]
^ abIvan J, Patricia G, Agustriawan D (June 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. doi:10.1016/j.compbiolchem.2021.107498. PMID33933781.
^Bjellqvist B, Hughes GJ, Pasquali C, Paquet N, Ravier F, Sanchez JC, et al. (October 1993). "The focusing positions of polypeptides in immobilized pH gradients can be predicted from their amino acid sequences". Electrophoresis. 14 (10): 1023–1031. doi:10.1002/elps.11501401163. PMID8125050.
^Bjellqvist B, Basse B, Olsen E, Celis JE (January 1994). "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. 15 (3–4): 529–539. doi:10.1002/elps.1150150171. PMID8055880.
^Bairoch A, Gattiker A, Wilkins MR, Gasteiger E, Duvaud S, Appel RD, et al. (2005). "Protein Identification and Analysis Tools on the ExPASy Server". The Proteomics Protocols Handbook. pp. 571–607. doi:10.1385/1-59259-890-0:571. ISBN978-1-58829-343-5.
^NCBI Gene entry on TMEM145 [11]. Retrieved September 18, 2024.
^ abWang L, Vasquez ML, Nuytemans K, Rajabli F, Whitehead P, Gearing M, et al. (December 2023). "Characterization of an African ancestry-specific protective allele of the APOE ε4 allele for Alzheimer's disease risk". Alzheimer's & Dementia. 19 (S12). doi:10.1002/alz.080287.
^Hattori Y, Kanamoto N, Kawano K, Iwakura H, Sone M, Miura M, et al. (September 2010). "Molecular characterization of tumors from a transgenic mouse adrenal tumor model: comparison with human pheochromocytoma". International Journal of Oncology. 37 (3): 695–705. doi:10.3892/ijo_00000719. PMID20664939.
