TMEM128

There are two isoforms of TMEM128.[11] Isoform 1 being the longest, consists of two variants differing in the 3' UTR region.[11] Variant 1 mRNA is 1,243 base pairs long while Variant 2 mRNA is 1,241 base pairs long.[5][12] Isoform 2 differs in the 5' UTR region of the protein and uses a different start codon location compared to the first variant.[11] This variant is longer at 1,785 base pairs and has a different N-terminus.[13]

TMEM128 is neighbored upstream by LYAR, Ly1 antibody reactive, and downstream by OTOP1, Otopetrin 1.[14]

TMEM128 Isoform 1 translates into a protein of 165 amino acids long, containing four transmembrane domains.[6] These domains exist at amino acids 49-69, 81-101, 119-139, and 144-164.[6] Isoform 1 is18,882 Da and has a pI of 6.27.[15] Using compositional analysis, the amino acid composition is similar to the average protein and there are no significant repeats in the protein.[15]

Predicted Secondary Structure for TMEM128[16]

Isoform 2 translates into a protein of 141 amino acids long, also containing four transmembrane domains.[17][18] Isoform 2 has a different molecular weight and isoelectric point compared to Isoform 1, coming in at 16,093 Da and having a pI of 6.8.[15]

Predicted secondary structure composition shows that most of the secondary structure consists of random coils.[19] No disulfide bonds are predicted to be present.[20]

Membrane topology of TMEM128 shows the four transmembrane domains, longer N-terminus, and shorter C terminus.

Predicted Tertiary Structure of TMEM128 as predicted by I-TASSER[21]

Predicted 3-D structure of TMEM128 as predicted by PHYRE2[22]

Tertiary structure is predicted to have four spiral domains in TMEM128. These domains are the transmembrane sections of the protein. For the above models, it is colored rainbow from N-terminus to C-terminus.

TMEM128 mRNA Expression by Tissue Type in Humans

Several promotors/enhancers of TMEM128 exist, with the GH04J00427 promotor located near the start of transcription, the GH04J004540 enhancer located downstream, and GH04J004264 enhancer located upstream of their target gene.[9][14] TMEM128 sequence also contains many binding sites for various transcription factors, including TATA box, CCAAT binding protein, and cAMP-responsive element binding protein.[23]

Expression of TMEM128 is also regulated at the gene level through differential tissue expression as seen with the image to the left. Red bars represent absolute expression while blue dots represent relative expression. TMEM128 is expressed highly in areas such as the adrenal gland and spinal cord, while is lower in areas such as the liver and bone marrow.[11]

Predicted Stem Loops for 3' UTR of TMEM128[24]

TMEM128 RNA Expression in a mouse brain[25]

Several miRNAs have binding sites on the 3' UTR of TMEM128 including:[26]

• hsa-miR-300
• hsa-miR-188-5p
• hsa-miR-506-3p
• hsa-miR-3163
• hsa-miR-548t-5p
• hsa-miR-3163
• hsa-miR-548t-5p
• hsa-miR-548az-5p

These miRNAs can participate in RNA silencing to prevent the expression of the mRNA.

Analyses of mouse brains show lack of region-specific expression throughout.[25]

In terms of protein regulation, TMEM128 contains many different post-translational domains including glycation,[27] phosphorylation,[28] SUMOylation,[29] and O-GlcNAc[30] as seen below:

Post-translational modification alters protein structure and can thus alter protein function and viability.

TMEM128 was found to be located in the Endoplasmic Reticulum membrane, with the N-terminus and C-terminus facing into the cytoplasm.[7][8]

There are no known paralogs of TMEM128.[33]

Orthologs of TMEM128 have not been found outside of Eukaryotes.[33] Inside of Eukaryotes, TMEM128 orthologs have been found in mammals, birds, and several fungi. Mammals contained the highest amount of conservation at no less than 71% conservation. The most distant ortholog detected was the Diversispora epigaea, a fungi. The transmembrane domains of this protein remain the most conserved throughout species, with key amino acids Trp51, Trp139, and Trp142 being conserved in all species with orthologous proteins. All information below was obtained through NCBI BLAST.[33]

Divergence of TMEM128 Relative to Fibrinogen Alpha Chain and Cytochrome C

The evolution rate is at a medium pace, slower than the fibrinogen alpha chain but faster than cytochrome c, suggesting neither positive or negative selection at this locus.

TMEM128 has been found to show moderate to strong positivity in some patients with carcinoma, with other types of cancer such as melanoma, glioma, breast, ovarian, renal, and pancreatic showing weak to moderate positivity.[42] TMEM128 also has been found to show low cancer specificity.[42]

TMEM128 expression is experimentally associated with presence of the ROR alpha1 protein, as TMEM128 was found in lower quantities when ROR alpha1 was deleted.[43][44]

TMEM128 expression was lowered following a null mutation of TAp63 in skin cells.[45][46]

TMEM128 expression was increased following a Trypanosoma cruzi infection.[47][48]

While it has been associated with several diseases such as Wolf-Hirschhorn Syndrome, no evidence exists for the exact cause of this syndrome and may only be correlation because of location on chromosome 4[9][49]

Several SNPs have been found in association with TMEM128:[50]