Transmembrane 202 protein (Homo sapiens, TMEM202) is encoded by the gene TMEM202 and is a member of the Claudin2 superfamily. Human paralogs include LIMP2, GSG1, CLDND2, NKG7. The specific function of TMEM202 has largely yet to be elucidated, but other Claudin2 superfamily proteins plays important roles in paracellular transport by contributing to the structure of gap junctions. In S. scrofa (wild boar), TMEM202 has been found to aid in sperm motility, fertilization, and spermatogenesis.
Gene
Location 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 genetic neighborhood is rather scarce, as HEXA is the gene nearest to TMEM202 and is found ~23,000 nucleotides upstream.
Expression TMEM202 demonstrates restricted and low expression in H. sapiens testis.
RNA and Transcriptional variants There exist four transcriptional variants of TMEM202 mRNA. +Properties of TMEM202 mRNA Transcript Variants.TMEM202 Transcript VariantAccession NumbermRNA length (nucleotides)5'UTR length (nucleotides)Exon 1Exon 2Exon 3Exon 4Exon 5Transcript variant 1NM_001080462131822YYYYYIsoform X1XM_0115214971326147X*YYYIsoform X2XM_024449910118622YYYXYIsoform X3XM_0115214991132169XXYYY '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).
TMEM202 protein 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). 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.
+Properties of TMEM202 Protein Variants.TMEM202 Protein VariantAccession NumberProtein Length (A.A)Approx. Molecular Weight Prior to PTMs (kDa)Exons presentSimilarity (%)Internal CompositionTMEM202 Variant 1NP_001073931.1273~31.21-5100L: (+) W: (+)TMEM202 Isoform X1XP_011519799.1234~26.8Part of 2; 3-585.7L: (+) W: (++)TMEM202 Isoform X2XP_024305678.1229~26.11-3, 583.9W: (+) A: (-) D: (-)TMEM202 Isoform X3XP_011519801.1162~18.53-558.6N/A 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).
TMEM202 Secondary Structure The figure to the right, TMEM202 Secondary Domains shows the predicted secondary structure of TMEM202, along with exon boundaries.
Gene Level Regulation
Expression pattern 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). 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.
Promoter region and transcription factor binding 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).
TMEM202 Transcription Factors Potentially Binding in Promoter Region. Transcription Factors NameBinding Site Location (Bases upstream - Strand)Binding ScoreFunction of Transcription FactorReason for IdentificationNFIC1 - Minus421Individually capable of activating transcriptionFunction; proximity to start codon; high conservationZSCAN4
(Twice)49 - Minus
134 - Plus461
609Regulates embryonic stem cell pluripotencyFunction relates to microarray studies; high binding score; appears twice in the promoter regionZBTB2475 - Minus554Involved in BMP2-induced transcription*High binding scoreTBP106 - Plus421Aids in the initiation of RNA polymerase II-dependent transcriptionFunction; high conservationDUXA
(Twice)109 - Plus
109 - Minus476
476Acts as a repressorFunction; binding sites on both the plus and minus strand at the same location; overlapping binding sequence with Tfcp2l1; appears twice in the promoter regionTfcp2l1115 - Plus446Facilitates establishment and maintenance of pluripotency in embryonic stem cellsFunction relates to microarray studies; overlapping binding sequence with DUXA, ELF3ELF3122 - Plus400Acts as an activatorFunction; overlapping binding sequence with Tfcp2l1TBX20124 - Minus449Acts as a transcriptional activator and repressorFunction; overlapping binding sequence with EOMESEOMES125 - Minus418Acts as transcriptional activator playing a crucial role during developmentFunction; overlapping binding sequence with TBX20Prdm5148 - Minus427Acts a transcriptional repressorFunctionMEIS2178 - Plus405Transcriptional regulation - stabilization of the homeoprotein-DNA complexFunction; overlapping binding sequence with FOXH1; moderate coservationFOXH1182 - Minus481Acts as an activatorFunction; overlapping binding sequence with MEIS2; moderate conservationKLF9205 - Plus403Selectively activates transcription when bound to GC box promoter elementsFunction; overlapping binding sequence with NR1D1NR1D1205 - Minus405Acts a transcriptional repressorFunction; overlapping binding sequence with KLF9Sox11221 - Plus421Acts as an activatorFunction; high coservationONECUT3245 - Minus508Acts as an activatorFunction; high binding score; overlapping binding sequence with ONECUT1ONECUT1247 - Minus346Acts as an activatorFunction; overlapping binding sequence with ONECUT3; moderate conservationFOXD3
(Twice)270 - Minus
364 - Minus446
467Acts as a transcriptional activator and repressorFunction; appears twice in the promoter region; overlapping binding sequence with HOXB13; high conservationHOXB13355 - Plus450Involved in the developmental regulatory system provides cells with positional identities along the anterior-posterior axisFunction; overlapping binding sequence with FOXD3Neurod2395 - Minus403Involved in neuronal determinationFunction (*) 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.
Protein level regulation
Post-translational modifications Predicted Post-Translational Modifications of TMEM202. Type of PTMNumber of SitesLocationSourceNotesGeneric phosphorylation29S13, S39, S254NetPhosLocations denoted were three highest scoredPhosphorylation2Y25, S245PhosphoPlusGlcNAc O-glycosylation2T107, S245DictyOGlycN-myristoylation2G61, G145MyHitAcetylation1K264PhosphoPlusN-linked glycosylation1N225NetNGlycN-linked glycosylation1N225ELMArginine and lysine propeptide cleavage sitesNoneNoneProPC-mannosylation sitesNoneNoneNetCGlycGPI AnchorsNoneNoneNetGPILikelihood not anchored by GPI - 0.993O-GalNAc (mucin type) glycosylation sitesNoneNoneNetOGlyc Different types of PTM’s were predicted using a variety of computational systems. Locations bolded were predicted by two or more unique systems.
TMEM202 homology and evolution
Paralogs of TMEM202 Four paralogs, LIMP2, GSG1, CLDND2, NKG7, have been discovered for TMEM202 and are outlined in the table below.
Paralogs of H. sapiens TMEM202. TMEM202 ParalogsGenus and SpeciesNameCommon NameAccession NumberSequence Length (amino acids)Sequence Identity to Human Protein (%)Sequence Similarity to Human Protein (%)Sequence Divergence (n)Corrected Sequence Divergence (m)Protein of InterestHomo sapiensTransmembrane Protein 202TMEM202NP_001073931.127310010000ParalogsHomo sapiensLens fiber membrane intrinsic protein isoform 2LIMP2NP_085915.221514.528.685.5193.1021537Homo sapiensProtein NKG7 isoform 1NKG7NP_005592.116514.327.985.7194.4910649Homo sapiensClaudin domain-containing protein 2CLDND2NP_689566.116714.225.485.8195.1928221Homo sapiensGerm cell-specific gene 1 protein isoform 1GSG1NP_112579.22858.515.391.5246.5104022 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 of TMEM202 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. TMEM202Taxonomic GroupGenus and SpeciesCommon NameAccession NumberMedian Date of Divergence (MYA)Sequence Length (amino acids)Sequence Identity to Human Protein (%)Sequence Similarity to Human Protein (%)Sequence Divergence (n)Corrected Sequence Divergence (m)MammalsPrimatesHomo sapiensHumanNP_001073931.10273100.0100.00.00.0LagomorphsOchotona princepsAmerican pikaXP_0045947728726358.371.441.754.0PerissodactylaDiceros bicornis minorSouth-central black rhinocerosXP_058396452.19427176.682.423.426.7ArtiodactylsSus scrofaWild boarXP_005666231.19427168.979.131.137.3ChiropteraRousettus aegyptiacusEgyptian fruit batXP_015982472.29428963.775.836.345.1EulipotyphlaCondylura cristataStar-nosed moleXP_004687557.19426761.773.738.348.3ProboscideansElephas maximus indicusIndian elephantXP_049761646.19926673.682.126.430.7DiprotodontiaVombatus ursinusCommon wombatXP_027713789.116028842.655.157.485.3Carnivorous marsupialsSarcophilus harrisiiTasmanian devilXP_031812217.116032438.450.861.695.7ReptiliaTestudinesChelydra serpentinaCommon snapping turtleKAG6921653.131919018.333.181.7169.8SquamataPodarcis lilfordiLilford's wall lizardCAI5781213.131919318.032.582.0171.5SquamataNaja najaIndian cobraKAG8143384.131915017.027.883.0177.2TestudinesChrysemys picta belliiPainted turtleXP_065430698.131948412.520.587.5207.9AvesPsittaciformesStrigops habroptilaKākāpōXP_030329880.131932014.220.385.8195.2GruiformesGrus japonensisRed-crowned craneGAB0205531.131923811.319.888.7218.0PasseriformesPseudopodoces humilisGround titXP_0055333823196417.711.292.3256.4AmphibiaAnuraEleutherodactylus coquiCommon coquíXP_066461729.135219220.131.979.9160.4AnuraAscaphus trueiCoastal tailed frogMEE6481875.135216815.727.284.3185.2UrodelaPleurodeles waltlIberian ribbed newtKAJ1132505.135217914.928.485.1190.4VertebrataCypriniformesCyprinus carpioCommon carpKTG06534.142922415.830.684.2184.5NotacanthiformesAldrovandia affinisGilbert's halosaurid fishKAJ8399001.142917314.228.485.8195.2