TMEM128

The TMEM128, or transmembrane protein 128, gene in humans is located on the minus strand at 4p16.3.{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM128|title=TMEM128 Gene - GeneCards {{!}} TM128 Protein {{!}} TM128 Antibody|website=www.genecards.org|access-date=2020-02-07}} TMEM128 contains 5 exons total and is 12,701 base pairs long including introns.{{Cite web|date=2020-03-02|title=Homo sapiens chromosome 4, GRCh38.p13 Primary Assembly|url=http://www.ncbi.nlm.nih.gov/nuccore/NC_000004.12}}

There are two isoforms of TMEM128.{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/85013|title=TMEM128 transmembrane protein 128 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2020-04-29}} Isoform 1 being the longest, consists of two variants differing in the 3' UTR region. Variant 1 mRNA is 1,243 base pairs long while Variant 2 mRNA is 1,241 base pairs long.{{Cite journal|date=2019-05-31|title=Homo sapiens transmembrane protein 128 (TMEM128), transcript variant 2, mRNA|url=http://www.ncbi.nlm.nih.gov/nuccore/NM_001297552.2}} Isoform 2 differs in the 5' UTR region of the protein and uses a different start codon location compared to the first variant. This variant is longer at 1,785 base pairs and has a different N-terminus.{{Cite web|date=2019-08-03|title=Homo sapiens transmembrane protein 128 (TMEM128), transcript variant 3, mRNA|url=http://www.ncbi.nlm.nih.gov/nuccore/NM_032927.3}}

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

TMEM128 Isoform 1 translates into a protein of 165 amino acids long, containing four transmembrane domains.{{Cite web|url=https://www.ncbi.nlm.nih.gov/protein/662033879|title=transmembrane protein 128 isoform 1 [Homo sapiens] - Protein - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2020-04-29}} These domains exist at amino acids 49-69, 81-101, 119-139, and 144-164. Isoform 1 is18,882 Da and has a pI of 6.27.{{Cite web|url=https://www.ebi.ac.uk/Tools/seqstats/saps/|title=SAPS < Sequence Statistics < EMBL-EBI|website=www.ebi.ac.uk|access-date=2020-04-29}} Using compositional analysis, the amino acid composition is similar to the average protein and there are no significant repeats in the protein.File:TMEM128 membrane domains.png

Isoform 2 translates into a protein of 141 amino acids long, also containing four transmembrane domains.{{Cite web|url=http://phobius.sbc.su.se/|title=Phobius|website=phobius.sbc.su.se|access-date=2020-04-29}}{{Cite web|url=https://www.ncbi.nlm.nih.gov/protein/14249720|title=transmembrane protein 128 isoform 2 [Homo sapiens] - Protein - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2020-04-29}} 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.

Predicted secondary structure composition shows that most of the secondary structure consists of random coils.{{Cite web|title=NPS@ : GOR4 secondary structure prediction|url=https://npsa-prabi.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsa_gor4.html|website=npsa-prabi.ibcp.fr|access-date=2020-05-02}} No disulfide bonds are predicted to be present.{{Cite web|title=DISULFIND - Cysteines Disulfide Bonding State and Connectivity Predictor|url=http://disulfind.dsi.unifi.it/|website=disulfind.dsi.unifi.it|access-date=2020-04-30}}

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

File:Tertiary Structure of TMEM128.jpg

File:TMEM128.png

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.

File:NCBI GEO TMEM128 Differential Expression by Tissue.png

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.{{Cite web|title=Human hg38 chr4:4,235,542-4,248,223 UCSC Genome Browser v397|url=https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr4:4235542-4248223&hgsid=830437121_GqnMSzJL0FfJIAD5KnPitZqTygoD|website=genome.ucsc.edu|access-date=2020-04-30}} TMEM128 sequence also contains many binding sites for various transcription factors, including TATA box, CCAAT binding protein, and cAMP-responsive element binding protein.{{Cite web|title=Transcription factor binding sites for GXP_149843|url=https://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=eaf7be30318d555e9e5b1474e5338bbe;PROM_ID=GXP_149843;GROUP=vertebrates;GROUP=others;ELDORADO_VERSION=E34R1811}}

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.

File:Secondary structure for 3' UTR of TMEM128.png

File:RNA Expression of TMEM128 in a mouse brain.png

Several miRNAs have binding sites on the 3' UTR of TMEM128 including:{{Cite web|title=miRDB - MicroRNA Target Prediction Database|url=http://www.mirdb.org/index.html|website=www.mirdb.org|access-date=2020-05-02}}

• 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.

In terms of protein regulation, TMEM128 contains many different post-translational domains including glycation,{{Cite web|url=http://www.cbs.dtu.dk/services/NetGlycate/|title=NetGlycate 1.0 server predication of glycation}} phosphorylation,{{Cite web|url=http://gps.biocuckoo.cn/wsresult.php|title=Kinase binding site prediction for TMEM128 |website=The CUCKOO Workgroup}} SUMOylation,{{Cite web|url=http://www.abcepta.com/sumoplot|title=SUMOplot Analysis Program Results for TMEM128}} and O-GlcNAc{{Cite web|url=http://www.cbs.dtu.dk/services/YinOYang/|title=YinOYand 1.2 prediction of O-GlcNAc sites for TMEM128}} 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.

There are no known paralogs of TMEM128.{{Cite web|title=BLAST: Basic Local Alignment Search Tool|url=https://blast.ncbi.nlm.nih.gov/Blast.cgi|website=blast.ncbi.nlm.nih.gov|access-date=2020-04-30}}

Orthologs of TMEM128 have not been found outside of Eukaryotes. 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.

File:Divergence of TMEM128.jpgThe 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 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
• GRB2, also known as Growth factor receptor-bound protein 2, which is involved in cell development and signal transduction.{{cite journal | vauthors = Grossmann A, Benlasfer N, Birth P, Hegele A, Wachsmuth F, Apelt L, Stelzl U | title = Phospho-tyrosine dependent protein-protein interaction network | journal = Molecular Systems Biology | volume = 11 | issue = 3 | pages = 794 | date = March 2015 | pmid = 25814554 | pmc = 4380928 | doi = 10.15252/msb.20145968}}
• BCL2L13, also known as B-cell lymphoma 2-like 13, which is an apoptosis facilitator{{cite journal | vauthors = Rolland T, Taşan M, Charloteaux B, Pevzner SJ, Zhong Q, Sahni N, Yi S, Lemmens I, Fontanillo C, Mosca R, Kamburov A, Ghiassian SD, Yang X, Ghamsari L, Balcha D, Begg BE, Braun P, Brehme M, Broly MP, Carvunis AR, Convery-Zupan D, Corominas R, Coulombe-Huntington J, Dann E, Dreze M, Dricot A, Fan C, Franzosa E, Gebreab F, Gutierrez BJ, Hardy MF, Jin M, Kang S, Kiros R, Lin GN, Luck K, MacWilliams A, Menche J, Murray RR, Palagi A, Poulin MM, Rambout X, Rasla J, Reichert P, Romero V, Ruyssinck E, Sahalie JM, Scholz A, Shah AA, Sharma A, Shen Y, Spirohn K, Tam S, Tejeda AO, Trigg SA, Twizere JC, Vega K, Walsh J, Cusick ME, Xia Y, Barabási AL, Iakoucheva LM, Aloy P, De Las Rivas J, Tavernier J, Calderwood MA, Hill DE, Hao T, Roth FP, Vidal M | display-authors = 6 | title = A proteome-scale map of the human interactome network | journal = Cell | volume = 159 | issue = 5 | pages = 1212–1226 | date = November 2014 | pmid = 25416956 | pmc = 4266588 | doi = 10.1016/j.cell.2014.10.050}}
• CLN8, also known as Ceroid-lipofuscinosis neuronal 8, which acts as a receptor in the Golgi and Endoplasmic Reticulum.{{cite journal | vauthors = Passantino R, Cascio C, Deidda I, Galizzi G, Russo D, Spedale G, Guarneri P | title = Identifying protein partners of CLN8, an ER-resident protein involved in neuronal ceroid lipofuscinosis | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1833 | issue = 3 | pages = 529–40 | date = March 2013 | pmid = 23142642 | doi = 10.1016/j.bbamcr.2012.10.030 | url = http://www.sciencedirect.com/science/article/pii/S0167488912003205 | doi-access = free}}
• RABAC1, also known as Prenylated Rab acceptor 1, which assists in vesicle transport.{{cite journal | vauthors = Huttlin EL, Bruckner RJ, Paulo JA, Cannon JR, Ting L, Baltier K, Colby G, Gebreab F, Gygi MP, Parzen H, Szpyt J, Tam S, Zarraga G, Pontano-Vaites L, Swarup S, White AE, Schweppe DK, Rad R, Erickson BK, Obar RA, Guruharsha KG, Li K, Artavanis-Tsakonas S, Gygi SP, Harper JW | display-authors = 6 | title = Architecture of the human interactome defines protein communities and disease networks | journal = Nature | volume = 545 | issue = 7655 | pages = 505–509 | date = May 2017 | pmid = 28514442 | pmc = 5531611 | doi = 10.1038/nature22366 | bibcode = 2017Natur.545..505H}}
• TMPRSS2, also known as Transmembrane protease, serine 2, which has a poorly understood function.{{cite journal | vauthors = Luck K, Kim DK, Lambourne L, Spirohn K, Begg BE, Bian W, Brignall R, Cafarelli T, Campos-Laborie FJ, Charloteaux B, Choi D, Coté AG, Daley M, Deimling S, Desbuleux A, Dricot A, Gebbia M, Hardy MF, Kishore N, Knapp JJ, Kovács IA, Lemmens I, Mee MW, Mellor JC, Pollis C, Pons C, Richardson AD, Schlabach S, Teeking B, Yadav A, Babor M, Balcha D, Basha O, Bowman-Colin C, Chin SF, Choi SG, Colabella C, Coppin G, D'Amata C, De Ridder D, De Rouck S, Duran-Frigola M, Ennajdaoui H, Goebels F, Goehring L, Gopal A, Haddad G, Hatchi E, Helmy M, Jacob Y, Kassa Y, Landini S, Li R, van Lieshout N, MacWilliams A, Markey D, Paulson JN, Rangarajan S, Rasla J, Rayhan A, Rolland T, San-Miguel A, Shen Y, Sheykhkarimli D, Sheynkman GM, Simonovsky E, Taşan M, Tejeda A, Tropepe V, Twizere JC, Wang Y, Weatheritt RJ, Weile J, Xia Y, Yang X, Yeger-Lotem E, Zhong Q, Aloy P, Bader GD, De Las Rivas J, Gaudet S, Hao T, Rak J, Tavernier J, Hill DE, Vidal M, Roth FP, Calderwood MA | display-authors = 6 | title = A reference map of the human binary protein interactome | journal = Nature | volume = 580 | issue = 7803 | pages = 402–408 | date = April 2020 | pmid = 32296183 | doi = 10.1038/s41586-020-2188-x | pmc = 7169983 | bibcode = 2020Natur.580..402L}}
• GJB5, also known as Gap junction beta-5 protein or connexin-31.1, which functions as a gap junction.

The biological function of TMEM128 is still poorly understood. As this is a transmembrane protein, common functions may include receptors, channels, or anchorage.{{Cite web|title=Membrane Proteins {{!}} BioNinja|url=https://ib.bioninja.com.au/standard-level/topic-1-cell-biology/13-membrane-structure/membrane-proteins.html|website=ib.bioninja.com.au|access-date=2020-02-07}} 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.{{Cite web|title=Phosphorylation - US|url=https://www.thermofisher.com/us/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/phosphorylation.html|website=www.thermofisher.com |access-date=2020-05-02}} TMEM128 also has a variety of interactions with other proteins as discussed above, suggesting it may have a broad range of action.

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.{{Cite web|title=Expression of TMEM128 in cancer - Summary - The Human Protein Atlas|url=https://www.proteinatlas.org/ENSG00000132406-TMEM128/pathology|website=www.proteinatlas.org|access-date=2020-05-02}} TMEM128 also has been found to show low cancer specificity.

TMEM128 expression is experimentally associated with presence of the ROR alpha1 protein, as TMEM128 was found in lower quantities when ROR alpha1 was deleted.{{Cite web|title=GDS3720 / ILMN_1248235|url=https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3720:ILMN_1248235|website=www.ncbi.nlm.nih.gov|access-date=2020-05-02}}{{cite journal | vauthors = Raichur S, Fitzsimmons RL, Myers SA, Pearen MA, Lau P, Eriksson N, Wang SM, Muscat GE | display-authors = 6 | title = Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle | journal = Nucleic Acids Research | volume = 38 | issue = 13 | pages = 4296–312 | date = July 2010 | pmid = 20338882 | pmc = 2910057 | doi = 10.1093/nar/gkq180 | url =}}

TMEM128 expression was lowered following a null mutation of TAp63 in skin cells.{{Cite web|title=GDS1435 / 107124_at|url=https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS1435:107124_at|website=www.ncbi.nlm.nih.gov|access-date=2020-05-02}}{{cite journal | vauthors = Koster MI, Kim S, Huang J, Williams T, Roop DR | title = TAp63alpha induces AP-2gamma as an early event in epidermal morphogenesis | journal = Developmental Biology | volume = 289 | issue = 1 | pages = 253–61 | date = January 2006 | pmid = 16324689 | doi = 10.1016/j.ydbio.2005.10.041}}

TMEM128 expression was increased following a Trypanosoma cruzi infection.{{Cite web|title=GDS5112 / 1448317_at|url=https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS5112:1448317_at|website=www.ncbi.nlm.nih.gov|access-date=2020-05-02}}{{cite journal | vauthors = Silva GK, Costa RS, Silveira TN, Caetano BC, Horta CV, Gutierrez FR, Guedes PM, Andrade WA, De Niz M, Gazzinelli RT, Zamboni DS, Silva JS | display-authors = 6 | title = Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1β response and host resistance to Trypanosoma cruzi infection | journal = Journal of Immunology | volume = 191 | issue = 6 | pages = 3373–83 | date = September 2013 | pmid = 23966627 | doi = 10.4049/jimmunol.1203293 | s2cid = 25181644 | doi-access = free}}

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{{cite journal | vauthors = Yang WX, Pan H, Li L, Wu HR, Wang ST, Bao XH, Jiang YW, Qi Y | display-authors = 6 | title = Analyses of Genotypes and Phenotypes of Ten Chinese Patients with Wolf-Hirschhorn Syndrome by Multiplex Ligation-dependent Probe Amplification and Array Comparative Genomic Hybridization | journal = Chinese Medical Journal | volume = 129 | issue = 6 | pages = 672–8 | date = March 2016 | pmid = 26960370 | pmc = 4804413 | doi = 10.4103/0366-6999.177996 | url = http://insights.ovid.com/crossref?an=00029330-201603200-00007 | doi-access = free}}

Several SNPs have been found in association with TMEM128:{{Cite web|title=SNP linked to Gene (geneID:85013) Via Contig Annotation|url=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|website=www.ncbi.nlm.nih.gov|access-date=2020-05-02}}

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Category:Transmembrane proteins