TMEM212

Last updated
TMEM212
Identifiers
Aliases TMEM212 , transmembrane protein 212
External IDs MGI: 2685410 HomoloGene: 28471 GeneCards: TMEM212
Orthologs
SpeciesHumanMouse
Entrez

389177

208613

Ensembl

ENSG00000186329

ENSMUSG00000043164

UniProt

A6NML5

Q8C6V3

RefSeq (mRNA)

NM_001164436

NM_001164437

RefSeq (protein)

NP_001157908

NP_001157909

Location (UCSC) Chr 3: 171.84 – 171.94 Mb Chr 3: 27.92 – 27.95 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Transmembrane protein 212 is a protein that in humans is encoded by the TMEM212 gene. [5] [6] The protein consists of five transmembrane domains and localizes in the plasma membrane and endoplasmic reticulum. [6] TMEM212 has orthologs in vertebrates but not invertebrates. [7] [8] TMEM212 has been associated with sporadic Parkinson's disease, facial processing, and adiposity in African Americans. [9] [10] [11]

Contents

Gene

Chromosome 3 with gene TMEM212 labeled Chromosome TMEM212.png
Chromosome 3 with gene TMEM212 labeled

The TMEM212 gene is on chromosome 3 at position 3q26.3 and is located on the plus strand. [6] [13] The gene is encoded from position 171,561,140 to 171,577,108. [14] Its longest isoform consists of 4 exons, a coding sequence of 1881 nucleotides, and an upstream in-frame stop codon. [5] The coding sequence is the 36-660 bases of the gene TMEM212. Other genes in the gene neighborhood include: PLD1, RNU6-348P and FNDC3B. [15]

Transcripts

The gene TMEM212 has 2 isoforms. [14] The mRNA splice variants of the TMEM212 vary at the last exon. One of the variants has spliced out part of the last exon—making it 537 nucleotides shorter. [14] This isofrom has a mRNA sequence of 1343 nucleotides. The later variant has not been acknowledged in NCBI. [13]

Figure 1: Conceptual Translation of Human Gene TMEM212 (NM_001164436.2) TMEM212 Conceptrual translaton.png
Figure 1: Conceptual Translation of Human Gene TMEM212 (NM_001164436.2)

Protein

TMEM212 has 5 transmembrane regions, making it a transmembrane protein. [5] [16] The 5 transmembrane regions are primarily non-polar amino acids. However, 2 of the transmembrane regions contain a polar, charged amino acid. [5] The protein is 194 amino acids long and has a calculated molecular weight of 21kDa. [6] The isoelectric point is at approximately a pH of 8. [17] [6] There are no internal repeats in the amino acid sequence of TMEM212. [18] [19] In addition, all amino acids are in normal abundance. [18] Human TMEM212 displays a similar molecular weight and isoelectric point to its orthologs as displayed in Table 1.

TMEM212 Protein Topology. Yellow represents potential signal cleavage peptide. Green presents amino acids with potential disulfide bonds. Blue numbers indicate transmembrane region. TMEM212 Protein Topology Corrected.jpg
TMEM212 Protein Topology. Yellow represents potential signal cleavage peptide. Green presents amino acids with potential disulfide bonds. Blue numbers indicate transmembrane region.

Table 1: TMEM212 Protein Characteristics in Humans and Orthologs

OrganismAccession #Molecular weightIsoelectric Point
HumanNP_001157908.121kDa8.2
MouseNP_001157909.121kDa7.6
Black SwanXP_035413176.121kDa6.1
Whale SharkXP_020372667.120 kDa9.1

Secondary and Tertiary Structure

Phyre 2 and Ali2D predict TMEM212 to have a secondary structure rich in alpha helices, specifically in the transmembrane regions. [20] [21] The alpha helices were conserved in orthologs from mammals to reptiles. [21] Additionally, DiANNA predicts TMEM212 to consist of 3 disulfide bonds between 6 cysteine amino acids: C46-C88, C105-C154, and C135-C16. [22] The tertiary structure has 5 regions within the membrane. [23] [16] [24]

Gene Level Regulation

Promoter

Microarray-assessed tissue expression patterns of Human TMEM212 from NCBI GEO GeoProfile TMEM212.png
Microarray-assessed tissue expression patterns of Human TMEM212 from NCBI GEO

According to Genomatix, TMEM212 has 3 possible promoters. However, the most likely promoter for TMEM212 is directly upstream the Gene of TMEM212 and is 1654 base pairs (GXP_277729). [25]

Expression

TMEM212 RNA is expressed lowly and ubiquitously in most tissue types (GDS1096). [26] TMEM212 is expressed at a slightly higher level in the ovaries, brain, lungs, heart, kidneys, testes. [14] TMEM212 was expressed in specific parts of the brain including the pons and trigeminal ganglion. [26] Other tissues with moderate expression included the adrenal cortex and the appendix. In all available RNA-sequencing data shows TMEM212 is found in the lungs. [13]

Transcript Level Regulation

The 5' untranslated region is 35 base pairs long. The 3' untranslated region is 1221 base pairs in length and is located from base 661 to 1881. [5] The lowest energy structure was predicted for the 5' UTR and 3' UTR. Because of the short length, the 5' UTR was predicted to have 1 stem-loop. The 3' UTR is predicted to have 17 stem-loops. [27]

Annotated RNA Secondary Structure of Human TMEM212 5' UTR 5'UTR Secondary Structure TMEM212.png
Annotated RNA Secondary Structure of Human TMEM212 5' UTR
Annotated RNA Secondary Structure of Human TMEM212 3'UTR Folded 3'UTR of TMEM212.png
Annotated RNA Secondary Structure of Human TMEM212 3'UTR

Protein Level Regulation

Modification

It is predicted that TMEM212 have two sulfation sites and one phosphorylation site. [28] [29] There is a potential cleavage signal peptide between amino acids 23 and 24. [30] The presence of the phosphorylation site and cleavage signal peptide is common among orthologs.

Schematic Model of Protein TMEM212. Blue boxes indicate transmembrane region. Red marker indicates phosphorylation site. Grey markers indicate sulfation site. Grey line indicates cleavage signal peptide. Schematic Model of TMEM212.png
Schematic Model of Protein TMEM212. Blue boxes indicate transmembrane region. Red marker indicates phosphorylation site. Grey markers indicate sulfation site. Grey line indicates cleavage signal peptide.

Subcellular Localization

The primary subcellular locations include the plasma membrane and endoplasmic reticulum. [6] The subcellular location of TMEM212 is conserved in orthologs. Immunofloursecent staining of TMEM212 antibodies show that TMEM212 is present in the nucleus, but the reason remains unknown. [31] TMEM212 is less abundant than most proteins in humans. [32]

Immunohistochemistry of stained prostate of TMEM212; Immunofluorescent staining of TMEM212 antibodies in human cell. Immunohistochemistry of stained prostate of TMEM212; Immunofluorescent staining of TMEM212 antibodies in human cell.jpg
Immunohistochemistry of stained prostate of TMEM212; Immunofluorescent staining of TMEM212 antibodies in human cell.

Evolution

Paralog

TMEM212 has one known paralog: Membrane-spanning 4 domains A7 (MS4A7). [6] The gene is located on chromosome 11 at 11q12.2. MS4A7 likely evolved from TMEM212 435-475 million years ago. This is shown on the right where the divergence rates of different proteins are compared.

Corrected Sequence Divergence vs Estimated Date of Divergence. Blue indicates TMEM212. Orange indicates Cytochrome C. Grey indicates Fibrinogen alpha. Yellow indicates paralog MS4A7. Black dashed line estimates MS4A7 divergence from TMEM212. Corrected Sequence Divergence vs Median Date of Divergence of TMEM212.png
Corrected Sequence Divergence vs Estimated Date of Divergence. Blue indicates TMEM212. Orange indicates Cytochrome C. Grey indicates Fibrinogen alpha. Yellow indicates paralog MS4A7. Black dashed line estimates MS4A7 divergence from TMEM212.
Multiple Sequence Alignment of strict orthologs of Human TMEM212 (NP_001157908). Amino acids shaded based on similarity. Orange boxes indicate transmembrane region. Strict Ortholog MSA of TMEM212.png
Multiple Sequence Alignment of strict orthologs of Human TMEM212 (NP_001157908). Amino acids shaded based on similarity. Orange boxes indicate transmembrane region.

Orthologs

TMEM212 in Homo sapiens is highly conserved. It is found in vertebrates but not invertebrates and has many orthologs including mammals, birds, reptiles, amphibians and fish. [7] [33] [8] Table 2 below shows orthologs of TMEM212 in mammals, reptiles, birds, amphibians and fish. As displayed in the multiple sequence alignment to the right, strict orthologs such as mammals and reptiles have highly conserved regions. Most of the conserved areas fell where transmembrane regions are localized. TMEM212 is evolving moderately quickly compared to reference sequences Cytochrome C and Fibrinogen alpha. This is shown to the right when comparing the divergence rates of TMEM212, MS4A7, Cytochrome C, and Fibrinogen Alpha.

Table 2: Selected Orthologs of Human TMEM212
Genus and SpeciesCommon NameTaxonomic GroupMedian Date of Divergence (MYA*)Accession #Sequence Length (aa)Sequence Identity to Human Protein (%)Sequence Similarity to Human Protein (%)
Homo sapiens HumansPrimates0NP_001157908.1194100.0100.0
Pan troglodytes ChimpanzeePrimates6.4* PNI77830.119499.599.5
Mus musculus House MouseRodentia89NP_001157909.119475.882.5
Orcinus orca Orca WhaleCetacea94XP_033285415.118376.884.5
Suricata suricatta MeercatCarnivora94XP_029796633.119574.681.0
Chelydra serpentina Common Snapping TurtleTestudines318KAG6939202.119464.974.2
Sceloporus undulatus Eastern Fence LizardSquamata318XP_042315631.118460.372.7
Crocodylus porosus Saltwater CrocodileCrocodylia318XP_019388281.118657.770.6
Python bivittatus Burmese PythonSerpentes318XP_007424363.218253.168.6
Cygnus atrat Black SwanAnseriformes318XP_035413176.119653.164.3
Apteryx mantelli North Island Brown KiwiStruthioniformes318XP_013800634.120049.159.3
Tyto alba Barn OwlStrigiformes318KFV59051.119844.956.6
Rhinatrema bivittatum Two-lined CaeciliansGymnophiona352XP_029472601.119761.475.1
Geotrypetes seraphini Gaboon CaecilianCaeciliidae352XP_033815221.119757.975.1
Xenopus laevis African Clawed FrogPipidae352XP_018119180.118351.570.6
Xenopus tropicalis Western Clawed FrogPipidae352XP_002931615.218750.070.1
Erpetoichthys calabaricus ReedfishPolypteriformes433XP_028648077.118750.064.4
Polyodon spathula American PaddlefishAcipenseriformes433XP_041127156.119150.063.9
Amia calva BowfinAmiiformes433MBN3298530.119843.757.8
Rhincodon typus Whale SharkOrectolobiformes465XP_020372667.118048.561.3
Amblyraja radiata Thorny SkateRajiformes465XP_032886885.119041.760.8
Petromyzon marinus Sea LampreyPetromyzontiformes599XP_032834400.119038.351.2

*MYA = Millions of Years Ago

Interacting Proteins

Three proteins were revealed to potentially interact with TMEM212: TMEM45A, GPR137C, and HNRNPL. [34] [35] [36] [37] These proteins were identified experimentally through co-expression or affinity capture-RNA. They were also identified using textmining. TMEM45A and GPR137 are also found in the plasma membrane, similar to TMEM212 making this interaction likely. [38] [39]

Table 3: Proteins that Interact with TMEM212

Abbreviated NameFull NameBasis of IdentificationFunction
TMEM45ATransmembrane protein 45Aco-expression, [35] textmining [34] enables protein binding
GPR137CG protein-coupled receptor 137Cco-expression, [35] textmining [34] involved in cell signaling and regulation of protein TORC1
HNRNPL Heterogeneous nuclear ribonucleoprotein L affinity capture-RNA [37] [36] formation, packaging and processing of mRNA

Clinical Significance

TMEM212 may be associated with adiposity in African Americans, facial processing, and sporadic Parkinson's disease. [9] [10] [11] Increases in TMEM212 (mrna or protein) and high BMI in African Americans have shown a link because SNPs at a locus near TMEM212 have been associated with increased adiposity. [11] Moreover, gene TMEM212 may also be involved in facial processing. Facial processing is genetically controlled, and in response to facial expressions, a common SNP found in TMEM212 led to the activation of the right fusiform gyrus area of the brain, which is important for facial processing. [10] This specifically happened at 3q26.31. The SNP is number rs12485367. People with a G alle had higher activation compared to C homozygotes. [10] TMEM212 may also be associated with Parkinson's Disease. Alterations in the SNP rs2270568 (Chromosome 3 position 172048861) in the TMEM212 gene changing the base T to C was associated with and increased incidence of Sporadic Parkinson's Disease. [9]

Related Research Articles

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<span class="mw-page-title-main">C16orf86</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">SMIM19</span> Protein-coding gene in the species Homo sapiens

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References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000043164 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  15. ↑ "GeneLoc Integrated Map for Chromosome 3: Search Results". genecards.weizmann.ac.il. Retrieved 2021-12-18.
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  17. ↑ "ExPASy - Compute pI/Mw tool". web.expasy.org. Retrieved 2021-12-15.
  18. 1 2 "SAPS < Sequence Statistics < EMBL-EBI". www.ebi.ac.uk. Retrieved 2021-12-18.
  19. ↑ Junier T, Pagni M (February 2000). "Dotlet: diagonal plots in a web browser". Bioinformatics. 16 (2): 178–179. doi: 10.1093/bioinformatics/16.2.178 . PMID   10842741.
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  23. ↑ "transmembrane protein 212 [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-12-18.
  24. ↑ "Protter - interactive protein feature visualization". wlab.ethz.ch. Retrieved 2021-12-18.
  25. ↑ "Genomatix Software Suite". Precigen Bioinformatics Germany. December 2021.
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  27. ↑ "RNA Folding Form". www.unafold.org. Retrieved 2021-12-18.
  28. ↑ Monigatti F, Gasteiger E, Bairoch A, Jung E (May 2002). "The Sulfinator: predicting tyrosine sulfation sites in protein sequences". Bioinformatics. 18 (5): 769–770. doi: 10.1093/bioinformatics/18.5.769 . PMID   12050077.
  29. ↑ "Services" . Retrieved 2021-12-18.
  30. ↑ "PSORT II Prediction". psort.hgc.jp. Retrieved 2021-12-18.
  31. ↑ "TMEM212 Antibody (PA5-65415)". www.thermofisher.com. Retrieved 2021-12-18.
  32. ↑ "PAXdb: Protein Abundance Database". pax-db.org. Retrieved 2021-12-18.
  33. ↑ "Query: Hsa_TMEM212". NCBI Blast.
  34. 1 2 3 Ren W, Aihara E, Lei W, Gheewala N, Uchiyama H, Margolskee RF, et al. (June 2017). "Transcriptome analyses of taste organoids reveal multiple pathways involved in taste cell generation". Scientific Reports. 7 (1): 4004. Bibcode:2017NatSR...7.4004R. doi:10.1038/s41598-017-04099-5. PMC   5479815 . PMID   28638111.
  35. 1 2 3 "TMEM212 protein (human) - STRING interaction network". string-db.org. Retrieved 2021-12-18.
  36. 1 2 Fei T, Chen Y, Xiao T, Li W, Cato L, Zhang P, et al. (June 2017). "Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing". Proceedings of the National Academy of Sciences of the United States of America. 114 (26): E5207–E5215. Bibcode:2017PNAS..114E5207F. doi: 10.1073/pnas.1617467114 . PMC   5495225 . PMID   28611215.
  37. 1 2 "TMEM212 Result Summary | BioGRID". thebiogrid.org. Retrieved 2021-12-18.
  38. ↑ "TMEM45A". www.genecards.org. Retrieved 2021-12-18.
  39. ↑ "GPR137C G protein-coupled receptor 137C [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-12-18.
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