TMEM62

Transmembrane protein 62 (TMEM62) is a protein which in Homo Sapiens is encoded by the TMEM62 gene. TMEM62 is an uncharacterized transmembrane protein predicted to be in a helicase related family The TMEM62 protein is predicted to be membrane-associated with several transmembrane helices and a compact, structured core. Expression analysis indicate that TMEM62 is variably and ubiquitously expressed at low to moderate levels across most tissues, with relatively higher expression in the brain and intentional tissues. The function of TMEM62 is unknown but computational and expression based analysis suggest a potential role in hydrolase activity, cell signaling, immune related processes, and gene regulation.

Gene The TMEM62 gene is located on human chromosome 15 (15q15.2). The gene spans 2,707 basepairs from the start of transcription to the poly(A) site and contains 14 exons in its longest transcript variant (transcript variant 1).

Transcripts +Table 1: Gene and Protein IsoformsIsoformTranscript AccessionSize (nt)Protein AccessionProtein Length (aa)aNM_024956.42,707NP_079232.3643b1NM_001347004.12,598NP_001333933.1513b2NM_001347005.22,595NP_001333934.1513b3NM_001347006.22,739NP_001333935.1513b4NM_001347007.22,627NP_001333936.1513c1NM_001347008.12,440NP_001333937.1511c2NM_001347009.12,552NP_001333938.1511c3NM_001347010.22,661NP_001333939.1511c4NM_001347011.22,549NP_001333940.1511c5NM_001347012.22,581NP_001333941.1511c6NM_001347013.22,693NP_001333942.1511d1NM_001347014.12,381NP_001333943.1478d2NM_001347015.22,634NP_001333944.1478d3NM_001347016.22,490NP_001333945.1478e1NM_001347017.22,444NP_001333946.1476e2NM_001347018.22,556NP_001333947.1476f1NM_001347019.12,298NP_001333948.1438f2NM_001347020.22,519NP_001333949.1438f3NM_001347021.22,439NP_001333950.1438f4NM_001347023.22,407NP_001333952.1438g1NM_001347024.12,305NP_001333953.1403g2NM_001347025.12,193NP_001333954.1403g3NM_001347026.22,414NP_001333955.1403g4NM_001347027.22,302NP_001333956.1403g5NM_001347028.22,446NP_001333957.1403g6NM_001347029.22,334NP_001333958.1403hNM_001347030.12,114NP_001333959.1389iNM_001347031.22,335NP_001333960.1519jNM_001347032.22,602NP_001333961.1608kNM_001347033.22,440NP_001333962.1554lNM_001347034.22,348NP_001333963.1400X1XM_047433101.12,584XP_047289057.1602X2XM_047433102.12,479XP_047289058.1567X3XM_047433103.12,335XP_047289059.1476X4XM_047433104.12,056XP_047289060.1435X5XM_047433105.11,977XP_047289061.1427X6XM_024450071.22,328XP_024305839.1424X7XM_024450072.21,997XP_024305840.1371

Protein

TMEM62 protein (isoform a) is 643 amino acids long with a theoretical molecular weight of ~73.1 kDa and a theoretical isoelectric point of 9.34. TMEM62 is enriched in hydrophobic amino acids (residues such as leucine, valine, isoleucine, phenylalanine, methionine, and alanine are enriched relative to average human proteins) consistent with its classification as a multi-pass transmembrane protein. SAPS analysis does not identify extensive low complexity regions. Short localized repeats involving proline, serine, and histidine are present but do not dominate the sequence and may contribute to local flexibility. Several short recurring motifs are present but no long tandem repeats or simple sequence repeats are detected, suggesting that TMEM62 is structurally constrained. Homology based analysis identified three significant motifs for the TMEM62 protein including TMEM62 C-terminal domain (TMEM62_C), TMEM62 Ig-like domain (Ig_TMM62), calcineurin-like phosphoesterase (Metallophos). These domains suggest involvement in cellular signaling, gene regulation, and adaptive immune responses. Some or all of these domains are conserved across vertebrate orthologs. The secondary protein structure prediction for TMEM62 suggests a very long continuous alpha helix at the N terminus followed by alternating alpha helices and beta sheets. The short beta sheets are clustered together with alpha helices between them and loops connecting them. There is a transition region where alpha helices and beta sheets are still alternating but it starts to become more helical and buried. From around the middle of the sequence to the C terminus there are almost only alpha helices that are strongly buried. No strong coiled segments were predicted. The tertiary protein structure prediction for TMEM62 has a very high confidence level of 91.75% (Fig.1).

Gene level regulation TMEM62 exhibits low tissue specificity, with variable and ubiquitous expression detected across many tissues at low to moderate levels. An expression cluster is found in the intestine and brain expression mainly occurs in the neurons (nucleosome) but overall there is low human brain regional specificity. RNA sequencing data shows relatively higher expression in the brain (cerebellum), colon, duodenum, gall  bladder, placenta, small intestine, and thyroid. Lower expression is observed in the ovary, pancreas, skin, and testis. Overall TMEM62 shows low cell type specificity with an expression cluster in adaptive immunity B-cells showing a mainly humoral response. Immunohistochemical staining of TMEM62 in the human kidney shows strong membranous positivity in tubule cells. The cytoplasmic expression of the TMEM62 protein is found in most tissues with membranous expression in few tissues including small intestines. TMEM62 protein is predicted to be located in the membrane and intracellular.

Protein level regulation TMEM62 is predicted to be localized in the endoplasmic reticulum with 43.5% confidence from PSORT II and a probability of 0.8308 from DeepLoc. Post-translational modification analyses predict one signal propeptide cleavage, four N-linked glycosylation sites, one O-glycosylation site, and various serine/threonine phosphorylation sites. It is predicted that TMEM62 has no C-mannosylation sites and is not GPI-anchored.

Homology and evolution

Paralogs No paralogs of TMEM62 have been identified in Homo sapiens.

Orthologs +Table 2: TMEM62 Orthologs and Related PropertiesGenus/speciesCommon nameTaxonomic groupMed. Date of divergence (mya)Accession numbersequence lengthsequence identitysequence similarityPrimataHomo sapiensHumanHominidae0NP_079232.3643100%100.00%MammaliaOtolemur garnettiiNorthern greater galagoGalagidae74XP_012661807.143760.7%63.8%Mus musculusHouse mouseMuridae87NP_780494.164383.2%91.0%Bos taurusDomestic cattleBovidae94NP_001192426.164383.8%91.0%ReptiliaChelonia mydasGreen sea turtleCheloniidae319EMP39578.140140.6%48.2%AmphibiaBombina bombinaFire bellied toadBombinatoridae352XP_053553778.164759.0%75.4%Ambystoma mexicanumAxolotylAmbystomatidae352XP_069475389.163859.4%73.3%Pleurodeles waltlLiberian ribbed newtSalamandridae352XP_069070694.163659.8%74.3%Bufotes viridisEuropean green toadBufonidae352CAN2020809.164455.7%72.0%Spea bombifronsPlains spadefoot toadScaphiopodidae352XP_053331252.164758.3%73.5%FishAtractosteus spatulaAligator garLepisosteidae429MBN3311900.164656.2%71.1%Amia calvaBowfinAmiidae429MBN3296123.165156.2%72.9%Astyanax mexicanusMexican tetraCharacidae429XP_049319844.165055.1%70.3%Pygocentrus nattereriRed bellied piranhaSerrasalmidae429XP_017549856.165054.9%69.2%

Paralogs TMEM62 does not have any paralogs.

Distant homologs Orthologs are detected across vertebrate lineages ranging from cartilaginous fish through ray-finned fish, amphibians, reptiles, and mammals, indicating conservation within vertebrates. No orthologs have been identified outside vertebrates, and there is no evidence of gene duplication within the mammalian lineage, as no paralogs have been detected. The TMEM62 gene likely emerged after the divergence of early chordates, as no orthologs have been detected after cartilaginous fish or in invertebrates.

Interacting proteins

Predicted protein interaction analyses suggest that TMEM62 may associate with several membrane associated and signaling related proteins. TMEM62 shows a predicted interaction with TMEM132A which is involved in embryonic and postnatal brain development that regulates cAMP-induced GFAP gene expression via STAT3 phosphorylation, suggesting a potential link between TMEM62 and neural signaling pathways. TMEM131L antagonizes canonical Wnt signaling by promoting lysosome-dependent degradation of activated LRP6 and regulates thymocyte proliferation, indicating a possible role for TMEM62 in growth or immune related signaling contexts. TMEM63C acts as an osmosensitive calcium permeable cation channel required for maintaining kidney glomerular filtration barrier integrity, suggesting TMEM62 involvement in membrane stress or ion-regulated processes. Other predicted protein interactions include ST8SIA5, CDHR2, SPRYD4, and SPRYD4. +Table 3: TMEM62 Interacting ProteinsProteinFull NameBasis of IdentificationScoreFunctionMore InformationTMEM132ATransmembrane protein 132ATextmining0.511May play a role in embryonic and postnatal development of the brainRegulates cAMP-induced GFAP gene expression via STAT3 phosphorylationTMEM164Transmembrane protein 164Co-expression Textmining0.488N/AN/AST8SIA5Alpha-2,8-sialyltransferase 8ETextmining0.483May be involved in the synthesis of gangliosidesBelongs to the glycosyltransferase 29 family.TMEM131LTransmembrane protein 131-likeTextmining0.467Membrane associated form that antagonizes canonical Wnt signaling by triggering lysosome dependent degradation of Wnt-activated LRP6Regulates thymocyte proliferationSPRYD4SPRY domain containing 4Experimentally determined Textmining Co-expression0.429N/AN/ATMEM63CCalcium permeable stress-gated cation channel 1Textmining0.405Acts as an osmosensitive calcium permeable cation channelRequired for the functional integrity of the kidney glomerular filtration barrierCDHR2Cadherin-related family member 2Gene fusions Textmining0.404Controls microvillar spacing, alignment, and packingMay also play a role in cell-cell adhesion and contact inhibition in epithelial cells

Clinical significance

Increased TMEM62 expression in cells caused tumor growth to slow, improved survival rates, and reduced tumor burden was found for high TMEM62 expression. TMEM62 likely acts through promoting tumor cell senescence (damaged cells stop dividing permanently) and influencing immune responses.

The structure of TMEM62 caused it to be predicted as a putative lipoxygenase that could modify arachidonic acid into signaling molecules to regulate inflammation and promote tissue remodeling

Figure 3 shows the expression of the TMEM62 gene changes in human monocytic cells when they are infected with the Sendai virus at a high and low dose. TMEM62 is expressed 92% more than other genes in the sample with a high dose, the low dose also shows expression in the low 90s, and the control shows expression around 85% on average. The graph shows the highest expression for the high dose of the virus and it decreases with the low dose and shows lowest expression in the control. However, the TMEM62 expression is fairly low in all groups overall.

Figure 4 shows how the expression of the TMEM62 gene changes in human monocyte derived dendritic cells under different cytokine treatments. The untreated dendritic cells have low TMEM62 expression compared to the treated groups and rank 69-74% compared to the expression of other genes in the sample. The IL-17A treatment greatly increases TMEM62 expression and the rank increases to 80%. The IL-17A + IFN-g treatment increases the expression even further with the highest expression ranking being 85%.

References