TMEM202

The TMEM202 gene spans 10,063 nucleotides on chromosome 15 located at 15q23-q24.1 and on the forward strand. The most complete isoform of TMEM202 (transcript variant 1) contains five exons. The [https://pmc.ncbi.nlm.nih.gov/articles/PMC117247/#:~:text=Specifically%2C%20neighborhoods%20composed%20of%20an,is%20a%20very%20wide%20range. genetic neighborhood] is rather scarce, as HEXA is the gene nearest to TMEM202 and is found ~23,000 nucleotides upstream.

TMEM202 demonstrates restricted and low expression in H. sapiens testis.{{Cite web |title=AceView: Gene:TMEM202, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView. |url=https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=TMEM202&submit=Go |access-date=2024-12-10 |website=www.ncbi.nlm.nih.gov}}

There exist four transcriptional variants of TMEM202 mRNA.

'Y' indicates the presence of the exon in the specific transcript variant, whereas 'X' denotes absence of the exon. '*' represents partial loss of exon two in isoform X1 (first thirty-six nucleotides). File:TMEM202 Predicted 3D Structure.pngs, three alpha helices, and one disulfide bond (all highlighted in yellow, except for the transmembrane domains) predicted in TMEM202 tertiary structure.

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TMEM202 is classified as a multi-pass protein as it consists of four transmembrane domains with helical structure (residue: 53-75, 121-141, 155-175, and 189-209) and one disordered region (242-273).{{Cite web |title=UniProt |url=https://www.uniprot.org/uniprotkb/A6NGA9/entry |access-date=2024-10-21 |website=www.uniprot.org}} TMEM202 protein is a member of the Claudin2 superfamily. Claudin proteins often form protein-protein interactions in epithelial and endothelial tissue, contributing to the scaffolding of the tight junction.

Similarity was calculated using Pairwise Sequence Alignments (PSAs) where all transcripts were aligned to transcript variant 1. The approximate molecular weight was calculated prior to post-translational modifications (PTMs), such as cleavages in the sequence or binding of additional molecules (e.g., phosphorylation, n-glycosylation). Emboss SAPS was used to determine relative composition of residues as compared to their database of H. sapiens samples. One (+/-) denotes one standard deviation away from the average, whereas two (++/--) indicate two standard deviations away from the average. Proteins with a (+/-) can be classified as rich or poor for that amino acid (e.g., TMEM202 Variant 1 is leucine- and tryptophan-rich).File:TMEM202 Protein Structural Units.jpg X-X indicates the transition between exons of the TMEM202 transcript, and the end of TMEM202 has been classified as disordered. A two-dimensional look at important regions of the TMEM202 protein. TM1-4 indicate regions of transmembrane domains, exon X-X indicates the transition between exons of the TMEM202 transcript, and the end of TMEM202 has been classified as disordered.|344x344px]]

The figure to the right, TMEM202 Secondary Domains shows the predicted secondary structure of TMEM202, along with exon boundaries.

The expression of TMEM202 was found to be restricted to the testis during a RNA-sequence study of normal adult human tissue (27 different tissues were analyzed from 95 individual human samples; RPKM = ~5).{{Cite web |title=TMEM202 transmembrane protein 202 [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/338949 |access-date=2024-12-12 |website=www.ncbi.nlm.nih.gov}} An additional RNA-seq study of human fetal tissue (six tissue types were sequenced from 35 human fetal samples between 10 and 20 weeks gestational time) found that TMEM202 is present in intestinal, lung, and stomach tissues at week 10 of gestation and in adrenal tissue at week 20.

The figure Annotated Promoter Sequence of Human TMEM202 shows potential binding locations for the most compatible transcription factors. The promoter region was defined as the 500 nucleotides directly upstream of transcription (denoted by a right pointing arrow).

File:Annotated Promoter Sequence of Human TMEM202.png TMEM202 Transcription Factors Potentially Binding in Promoter Region.{{Cite web |title=JASPAR: An open-access database of transcription factor binding profiles |url=https://jaspar.elixir.no/ |access-date=2024-12-12 |website=jaspar.elixir.no}}{{Cite web |title=UniProt |url=https://www.uniprot.org/ |access-date=2024-12-12 |website=www.uniprot.org}}

(*) Indicates hypothesized function. A higher binding score suggests a higher likelihood that the transcription factor will bind to the sequence when present—binding scores were calculated by the Jaspar Database. This is a non-exhaustive list of potential transcription factors that may bind to TMEM202, but presents transcription factors with the highest binding score or potentially illuminating qualities within the 500 base promoter region.

Predicted Post-Translational Modifications of TMEM202.{{Cite web |title=NetPhos 3.1 - DTU Health Tech - Bioinformatic Services |url=https://services.healthtech.dtu.dk/services/NetPhos-3.1/ |access-date=2024-12-12 |website=services.healthtech.dtu.dk}}{{Cite web |title=DictyOGlyc 1.1 - DTU Health Tech - Bioinformatic Services |url=https://services.healthtech.dtu.dk/services/DictyOGlyc-1.1/ |access-date=2024-12-12 |website=services.healthtech.dtu.dk}}{{Cite web |title=NetNGlyc 1.0 - DTU Health Tech - Bioinformatic Services |url=https://services.healthtech.dtu.dk/services/NetNGlyc-1.0/ |access-date=2024-12-12 |website=services.healthtech.dtu.dk}}{{Cite web |title=ELM - unknown |url=http://elm.eu.org/cgimodel.py?fun=smartResult&userId=QiKOqEAdet&EXPECT_CUTOFF=100&r=1&bg=on |access-date=2024-12-12 |website=elm.eu.org}}{{Cite web |title=TMEM202 (human) |url=https://www.phosphosite.org/proteinAction.action?id=3710588&showAllSites=true |access-date=2024-12-12 |website=www.phosphosite.org}}

Different types of PTM’s were predicted using a variety of computational systems. Locations bolded were predicted by two or more unique systems.

File:PTM of TMEM202.png

Four paralogs, LIMP2, GSG1, CLDND2, NKG7, have been discovered for TMEM202 and are outlined in the table below.

Paralogs of H. sapiens TMEM202.{{Cite web |title=BLAST: Basic Local Alignment Search Tool |url=https://blast.ncbi.nlm.nih.gov/Blast.cgi |access-date=2024-12-12 |website=blast.ncbi.nlm.nih.gov}}{{Cite web |title=National Center for Biotechnology Information |url=https://www.ncbi.nlm.nih.gov/ |access-date=2024-12-12 |website=www.ncbi.nlm.nih.gov |language=en}}{{Cite web |title=TimeTree :: The Timescale of Life |url=https://timetree.org/ |access-date=2024-12-12 |website=timetree.org |language=en}}

Sequences characterized as paralogs were aligned to TMEM202 via pairwise analysis (PSA). The results of the PSA gave percent identity and similarity values, which were also used to calculate the sequence divergence value (n) and corrected sequence divergence value (m). Estimated median date of divergence is based on predicted values found on TimeTree.

Orthologs were found using the NCBI Blast database by searching for proteins with similar sequences to the H. sapiens TMEM202 protein. All taxia with sequenced proteins, including bacteria, fungi and plants were searched; however, bony fish were found to be the most diverged species to have orthologous proteins. Orthologs were also found in amphibians, birds, reptiles, and mammals. Orthologs are characterized in the table below:

Orthologs of H. sapiens TMEM202.

Sequences characterized as orthologs were aligned to TMEM202 via pairwise analysis (PSA). The results of the PSA gave percent identity and similarity values, which were also used to calculate the sequence divergence value (n) and corrected sequence divergence value (m). Estimated median date of divergence is based on predicted values found on TimeTree.

The evolutionary history of TMEM202 appears to have begun approximately 429 years ago as orthologs of the protein were found in species of bony fish. Since then, TMEM202 has evolved in species of amphibians, reptiles, birds, and mammals. This evolution is quantified in Evolutionary History of TMEM202 compared to Fibrinogen a, cyctochrome C, where corrected sequence divergence of TMEM202 orthologs was graphed over time in comparison to fibrinogen a and cytochrome c.

{{Cite web |title=National Center for Biotechnology Information |url=https://www.ncbi.nlm.nih.gov/ |access-date=2024-12-13 |website=www.ncbi.nlm.nih.gov |language=en}}{{Cite web |title=TimeTree :: The Timescale of Life |url=https://timetree.org/ |access-date=2024-12-13 |website=timetree.org |language=en}}File:Evolutionary History of TMEM202.pngFibrinogen alpha (a) is a fast-evolving protein as compared to cytochrome c, a slow-evolving protein. Across its evolution, TMEM202 has undergone numerous amino acid mutations, as it has ascertained mutations at a similar rate to fibrinogen alpha. For this reason, TMEM202 can be considered a fast-evolving protein.File:TMEM202 Unrooted Phylogenetic Tree.pngTo the left, Unrooted Phylogenetic Tree of Homo sapiens TMEM202 and its Orthologous Species, helps visualize divergence of some orthologs from humans. Species were further classified into mammals, aves, amphibians, and reptiles.

STRING Network revealed proteins found to interact with TMEM202 and are detailed in the table below. Along with those proteins, are kinases predicted to phosphorylate TMEM202.

{{cite web | work = Genecards: The Human Gene Database | title = Entry on SPATA31D1 | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=SPATA31D1 }}{{cite web | work = Genecards: The Human Gene Database | title = Entry on CFAP45 | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=CFAP45 }}{{cite web | work = Genecards: The Human Gene Database | title = Entry on SPACA1 | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=SPACA1 }}{{cite journal | vauthors = Shah K, Lahiri DK | title = Cdk5 activity in the brain - multiple paths of regulation | journal = Journal of Cell Science | volume = 127 | issue = Pt 11 | pages = 2391–400 | date = June 2014 | pmid = 24879856 | doi = 10.1242/jcs.147553 | url = | pmc = 4038939 }}{{Cite web |title=CDK1 cyclin dependent kinase 1 [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/983 |access-date=2024-12-12 |website=www.ncbi.nlm.nih.gov |language=en}}

There exist many identified SNPs in the TMEM202 gene. Found in the table below include six of the most common to occur within the promoter region and coding sequence of TMEM202.

{{Cite web |title=Home - SNP - NCBI |url=https://www.ncbi.nlm.nih.gov/snp/ |access-date=2024-12-12 |website=www.ncbi.nlm.nih.gov}}{{Cite web |title=Human hg38 chr15:72,398,305-72,408,367 UCSC Genome Browser v474 |url=https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr15:72398305-72408367&hgsid=2391197933_4iGlnJxXpMANHCjUNQe01OWjesle |access-date=2024-12-12 |website=genome.ucsc.edu}}

A small subset of the SNPs may have functional influences on TMEM202 based on where they occur. The SNP, rs16956904 at base 631, is within the fourth transmembrane region. While this is an area of importance, both the normal and SNP variation result in a hydrophobic amino acid. This could explain why no clinical / phenotypic discrepancies have been observed. SNP rs114543781, 284 bases upstream is present where transcription factor HOXB13 is predicted to bind. This transcription factor is involved in the developmental regulatory system that provides cells with positional identities along the anterior-posterior axis. SNP rs74343303, 193 bases upstream also interferes with FOXD3 binding. FOXD3 has the ability to act as a transcriptional activator and repressor.

File:Conceptual Translation of Human TMEM202.pdf

Key found on page 2.

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