Biology:TMEM128

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TMEM128, also known as Transmembrane Protein 128, is a protein that in humans is encoded by the TMEM128 gene. TMEM128 has three variants, varying in 5' UTR's and start codon location.[1] TMEM128 contains four transmembrane domains and is localized in the Endoplasmic Reticulum membrane.[2][3][4] TMEM128 contains a variety of regulation at the gene, transcript, and protein level. While the function of TMEM128 is poorly understood, it interacts with several proteins associated with the cell cycle, signal transduction, and memory.

Gene

The TMEM128, or transmembrane protein 128, gene in humans is located on the minus strand at 4p16.3.[5] TMEM128 contains 5 exons total and is 12,701 base pairs long including introns.[1][5][6]

Transcripts

There are two isoforms of TMEM128.[7] Isoform 1 being the longest, consists of two variants differing in the 3' UTR region.[7] Variant 1 mRNA is 1,243 base pairs long while Variant 2 mRNA is 1,241 base pairs long.[1][8] Isoform 2 differs in the 5' UTR region of the protein and uses a different start codon location compared to the first variant.[7] This variant is longer at 1,785 base pairs and has a different N-terminus.[9]

Neighboring genes

TMEM128 is neighbored upstream by LYAR, Ly1 antibody reactive, and downstream by OTOP1, Otopetrin 1.[10]

Protein

Isoform 1

TMEM128 Isoform 1 translates into a protein of 165 amino acids long, containing four transmembrane domains.[2] These domains exist at amino acids 49-69, 81-101, 119-139, and 144-164.[2] Isoform 1 is18,882 Da and has a pI of 6.27.[11] Using compositional analysis, the amino acid composition is similar to the average protein and there are no significant repeats in the protein.[11]

Predicted Secondary Structure for TMEM128[12]

Isoform 2

Isoform 2 translates into a protein of 141 amino acids long, also containing four transmembrane domains.[13][14] 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.[11]

Secondary structure

Secondary Structure Composition
Type of Secondary Structure Number of Amino Acids Percent Composition
Alpha Helix 34 20.61%
Extended Strand 59 35.76%
Random Coil 72 43.64%

Predicted secondary structure composition shows that most of the secondary structure consists of random coils.[15] No disulfide bonds are predicted to be present.[16]

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

Tertiary structure

Predicted Tertiary Structure of TMEM128 as predicted by I-TASSER[17]
Predicted 3-D structure of TMEM128 as predicted by PHYRE2[18]

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.

Regulation of expression

Gene level regulation

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.[5][10] TMEM128 sequence also contains many binding sites for various transcription factors, including TATA box, CCAAT binding protein, and cAMP-responsive element binding protein.[19]

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.[7]

Transcript level regulation

Predicted Stem Loops for 3' UTR of TMEM128[20]
TMEM128 RNA Expression in a mouse brain[21]

Several miRNAs have binding sites on the 3' UTR of TMEM128 including:[22]

  • 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.[21]

Protein level regulation

In terms of protein regulation, TMEM128 contains many different post-translational domains including glycation,[23] phosphorylation,[24] SUMOylation,[25] and O-GlcNAc[26] as seen below:

Modification Amino Acid Number
Phosphorylation 3, 4, 52, 124, l35, 162
Glycation 70, 73, 115
Nuclear Export Signal[27] 88-95
SUMOylation 39-42, 115-118, 161-165
O-GlcNAc 3, 4, 34, 35, 123
Acetylation[28] 40, 41, 43, 73

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

Sub-cellular localization

TMEM128 was found to be located in the Endoplasmic Reticulum membrane, with the N-terminus and C-terminus facing into the cytoplasm.[3][4]

Evolution

Paralogs

There are no known paralogs of TMEM128.[29]

Orthologs

Orthologs of TMEM128 have not been found outside of Eukaryotes.[29] 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 fungus. 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.[29]

Orthologs of TMEM128
Genus and Species Common Name Date of Divergence (MYA)[30] Accession Number Sequence Length Sequence Identity
Homo sapiens Human 0 NP_001284480.1 165 100%
Rhinopithecus roxellana Golden Snub-Nosed Monkey 28.81 XP_010355887.2 165 97%
Mus musculus House Mouse 89 NP_001343889.1 163 81%
Microtus ochrogaster Prairie Vole 89 XP_005366021 164 80%
Ovis aries Sheep 94 XP_014952114.2 165 83%
Vulpes vulpes Red Fox 94 XP_025854088.1 165 82%
Pteropus vampyrus Large Flying Fox 94 XP_011372965.1 165 81%
Orcinus orca Killer Whale 94 XP_004269680.1 165 81%
Monodelphis domestica Gray short-tailed opossum 160 XP_001371407.3 170 71%
Taeniopygia guttata Zebra Finch 318 XP_002193492.3 173 68%
Alligator sinensis Chinese Alligator 318 XP_006016834.1 172 67%
Pogona vitticeps Central Bearded Dragon 318 XP_020633929.1 163 62%
Xenopus laevis African Clawed Frog 351.7 NP_001084889.1 166 52%
Orbicella faveolata Mountainous Star Coral 687 XP_020610022.1 171 38%
Exaiptasia pallida Sea Anenmone 687 XP_028518835.1 169 36%
Octopus vulgaris Common Octopus 736 XP_029645279.1 184 33%
Brachionus plicatilis N/A 736 RNA25638.1 170 28%
Crassostrea virginica Eastern Oyster 736 XP_022343076.1 200 28%
Diversispora epigaea N/A 1017 RHZ70611.1 176 24%

Mutation rate

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.

Interacting proteins

TMEM128 has been found via yeast two-hybrid assays to interact with:

  • Arc/Arg 3.1, also known as Activity-regulated cytoskeleton-associated protein, which helps facilitate learning and memory processes[3]
  • GRB2, also known as Growth factor receptor-bound protein 2, which is involved in cell development and signal transduction.[31]
  • BCL2L13, also known as B-cell lymphoma 2-like 13, which is an apoptosis facilitator[32]
  • CLN8, also known as Ceroid-lipofuscinosis neuronal 8, which acts as a receptor in the Golgi and Endoplasmic Reticulum.[33]
  • RABAC1, also known as Prenylated Rab acceptor 1, which assists in vesicle transport.[34]
  • TMPRSS2, also known as Transmembrane protease, serine 2, which has a poorly understood function.[35]
  • GJB5, also known as Gap junction beta-5 protein or connexin-31.1, which functions as a gap junction.[35]

Function

The biological function of TMEM128 is still poorly understood. As this is a transmembrane protein, common functions may include receptors, channels, or anchorage.[36] Because TMEM128 has post-translational modification sites, alternative protein states may be present that permit TMEM128 to have different forms. For example, phosphorylation of TMEM128 may make it bind to different substrates through conformational change.[37] TMEM128 also has a variety of interactions with other proteins as discussed above, suggesting it may have a broad range of action.

Clinical significance

Cancer

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.[38] TMEM128 also has been found to show low cancer specificity.[38]

Skeletal muscle

TMEM128 expression is experimentally associated with presence of the ROR alpha1 protein, as TMEM128 was found in lower quantities when ROR alpha1 was deleted.[39][40]

Skin

TMEM128 expression was lowered following a null mutation of TAp63 in skin cells.[41][42]

Cardiac muscle

TMEM128 expression was increased following a Trypanosoma cruzi infection.[43][44]

Neurological diseases

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[5][45]

Mutations

Several SNPs have been found in association with TMEM128:[46]

Key SNPs of TMEM128
mRNA Position Amino Acid Position dbSNP rs# Reference Allele SNP Allele Function
169 43 rs771177507 A C Missense
186 49 rs146625911 A C Missense
204 55 rs1434953873 G T Missense
270 77 rs13135886 A G Missense
463 139 rs757745482 T C Missense
466 142 rs1213450146 G A Nonsense
512 158 rs202215273 G A, T Missense

References

  1. ↑ 1.0 1.1 1.2 Transmembrane Protein 128, transcript variant 1, mRNA. March 1, 2020. https://www.ncbi.nlm.nih.gov/nuccore/NM_001297551.2. 
  2. ↑ 2.0 2.1 2.2 "transmembrane protein 128 isoform 1 [Homo sapiens - Protein - NCBI"]. https://www.ncbi.nlm.nih.gov/protein/662033879. 
  3. ↑ 3.0 3.1 3.2 Gutzmann, Jakob (2013). "Characterization of Tmem128 – An activity regulated ER protein, interacting with the immediate early gene Arc/Arg3.1". Refubium. doi:10.17169/refubium-14701. https://refubium.fu-berlin.de/handle/fub188/10503. 
  4. ↑ 4.0 4.1 "PSORT II Prediction". https://psort.hgc.jp/form2.html. 
  5. ↑ 5.0 5.1 5.2 5.3 "TMEM128 Gene - GeneCards | TM128 Protein | TM128 Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM128. 
  6. ↑ "Homo sapiens chromosome 4, GRCh38.p13 Primary Assembly" (in en-US). 2020-03-02. http://www.ncbi.nlm.nih.gov/nuccore/NC_000004.12. 
  7. ↑ 7.0 7.1 7.2 7.3 "TMEM128 transmembrane protein 128 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/85013. 
  8. ↑ (in en-US) Homo sapiens transmembrane protein 128 (TMEM128), transcript variant 2, mRNA. 2019-05-31. http://www.ncbi.nlm.nih.gov/nuccore/NM_001297552.2. 
  9. ↑ "Homo sapiens transmembrane protein 128 (TMEM128), transcript variant 3, mRNA" (in en-US). 2019-08-03. http://www.ncbi.nlm.nih.gov/nuccore/NM_032927.3. 
  10. ↑ 10.0 10.1 "Human hg38 chr4:4,235,542-4,248,223 UCSC Genome Browser v397". https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr4:4235542-4248223&hgsid=830437121_GqnMSzJL0FfJIAD5KnPitZqTygoD. 
  11. ↑ 11.0 11.1 11.2 "SAPS < Sequence Statistics < EMBL-EBI". https://www.ebi.ac.uk/Tools/seqstats/saps/. 
  12. ↑ "Protter - interactive protein feature visualization". http://wlab.ethz.ch/protter/start/. 
  13. ↑ "Phobius". http://phobius.sbc.su.se/. 
  14. ↑ "transmembrane protein 128 isoform 2 [Homo sapiens - Protein - NCBI"]. https://www.ncbi.nlm.nih.gov/protein/14249720. 
  15. ↑ "NPS@ : GOR4 secondary structure prediction". https://npsa-prabi.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsa_gor4.html. 
  16. ↑ "DISULFIND - Cysteines Disulfide Bonding State and Connectivity Predictor". http://disulfind.dsi.unifi.it/. 
  17. ↑ "I-TASSER server for protein structure and function prediction". https://zhanglab.ccmb.med.umich.edu/I-TASSER/. 
  18. ↑ "PHYRE2 Protein Fold Recognition Server". http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index. 
  19. ↑ "Transcription factor binding sites for GXP_149843". https://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=eaf7be30318d555e9e5b1474e5338bbe;PROM_ID=GXP_149843;GROUP=vertebrates;GROUP=others;ELDORADO_VERSION=E34R1811. 
  20. ↑ "miRDB - MicroRNA Target Prediction Database". http://www.mirdb.org/cgi-bin/search.cgi. 
  21. ↑ 21.0 21.1 "Experiment Detail :: Allen Brain Atlas: Mouse Brain". https://mouse.brain-map.org/experiment/show/68080707. 
  22. ↑ "miRDB - MicroRNA Target Prediction Database". http://www.mirdb.org/index.html. 
  23. ↑ "NetGlycate 1.0 server predication of glycation". http://www.cbs.dtu.dk/services/NetGlycate/. 
  24. ↑ "Kinase binding site prediction for TMEM128". http://gps.biocuckoo.cn/wsresult.php. 
  25. ↑ "SUMOplot Analysis Program Results for TMEM128". http://www.abcepta.com/sumoplot. 
  26. ↑ "YinOYand 1.2 prediction of O-GlcNAc sites for TMEM128". http://www.cbs.dtu.dk/services/YinOYang/. 
  27. ↑ "NetNES 1.1 Server". http://www.cbs.dtu.dk/services/NetNES/. 
  28. ↑ ":::PAIL - Prediction of Acetylation on Internal Lysines:::". http://bdmpail.biocuckoo.org/prediction.php. 
  29. ↑ 29.0 29.1 29.2 "BLAST: Basic Local Alignment Search Tool". https://blast.ncbi.nlm.nih.gov/Blast.cgi. 
  30. ↑ "TimeTree :: The Timescale of Life". http://www.timetree.org/. 
  31. ↑ "Phospho-tyrosine dependent protein-protein interaction network". Molecular Systems Biology 11 (3): 794. March 2015. doi:10.15252/msb.20145968. PMID 25814554. 
  32. ↑ "A proteome-scale map of the human interactome network". Cell 159 (5): 1212–1226. November 2014. doi:10.1016/j.cell.2014.10.050. PMID 25416956. 
  33. ↑ "Identifying protein partners of CLN8, an ER-resident protein involved in neuronal ceroid lipofuscinosis". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1833 (3): 529–40. March 2013. doi:10.1016/j.bbamcr.2012.10.030. PMID 23142642. http://www.sciencedirect.com/science/article/pii/S0167488912003205. 
  34. ↑ "Architecture of the human interactome defines protein communities and disease networks". Nature 545 (7655): 505–509. May 2017. doi:10.1038/nature22366. PMID 28514442. Bibcode: 2017Natur.545..505H. 
  35. ↑ 35.0 35.1 "A reference map of the human binary protein interactome". Nature 580 (7803): 402–408. April 2020. doi:10.1038/s41586-020-2188-x. PMID 32296183. Bibcode: 2020Natur.580..402L. 
  36. ↑ "Membrane Proteins | BioNinja". https://ib.bioninja.com.au/standard-level/topic-1-cell-biology/13-membrane-structure/membrane-proteins.html. 
  37. ↑ "Phosphorylation - US" (in en). https://www.thermofisher.com/us/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/phosphorylation.html. 
  38. ↑ 38.0 38.1 "Expression of TMEM128 in cancer - Summary - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000132406-TMEM128/pathology. 
  39. ↑ "GDS3720 / ILMN_1248235". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3720:ILMN_1248235. 
  40. ↑ "Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle". Nucleic Acids Research 38 (13): 4296–312. July 2010. doi:10.1093/nar/gkq180. PMID 20338882. 
  41. ↑ "GDS1435 / 107124_at". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS1435:107124_at. 
  42. ↑ "TAp63alpha induces AP-2gamma as an early event in epidermal morphogenesis". Developmental Biology 289 (1): 253–61. January 2006. doi:10.1016/j.ydbio.2005.10.041. PMID 16324689. 
  43. ↑ "GDS5112 / 1448317_at". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS5112:1448317_at. 
  44. ↑ "Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1β response and host resistance to Trypanosoma cruzi infection". Journal of Immunology 191 (6): 3373–83. September 2013. doi:10.4049/jimmunol.1203293. PMID 23966627. 
  45. ↑ "Analyses of Genotypes and Phenotypes of Ten Chinese Patients with Wolf-Hirschhorn Syndrome by Multiplex Ligation-dependent Probe Amplification and Array Comparative Genomic Hybridization". Chinese Medical Journal 129 (6): 672–8. March 2016. doi:10.4103/0366-6999.177996. PMID 26960370. PMC 4804413. http://insights.ovid.com/crossref?an=00029330-201603200-00007. 
  46. ↑ "SNP linked to Gene (geneID:85013) Via Contig Annotation". https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?geneId=85013&ctg=NT_006051.19&mrna=NM_001297551.1&prot=NP_001284480.1&orien=reverse. 



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