TMEM81

Transmembrane Protein 81 or TMEM81 is a protein that in humans is encoded by the TMEM81 gene. TMEM81 is a poorly-characterized transmembrane protein which contains an extracellular immunoglobulin domain.[6]

TMEM81
Identifiers
AliasesTMEM81, HC3107, KVLA2788, UNQ2788, transmembrane protein 81
External IDsMGI: 1921876 HomoloGene: 12579 GeneCards: TMEM81
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1q32.1Start205,083,129 bp[1]
End205,084,460 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

388730

74626

Ensembl

ENSG00000174529

ENSMUSG00000048174

UniProt

Q6P7N7

Q9D5K1

RefSeq (mRNA)

NM_203376

NM_029025

RefSeq (protein)

NP_976310

NP_083301

Location (UCSC)Chr 1: 205.08 – 205.08 MbChr 1: 132.51 – 132.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Predicted tertiary structure of TMEM81 (extracellular region only) from I-TASSER.[5] The structure was visualized using PyMol.

Gene

TMEM81 is also known as HC3107, UNQ2788, KVLA2788,[6] or MGC75217.[7] In humans, TMEM81 is located on chromosomal band 1q32.1 between the genes CNTN2 and RBBP5 on the reverse strand.[8] The TMEM81 gene is 1332 base pairs long and encodes one transcript containing a single exon.[6][9]

The predicted promoter region (GXP_180875) for TMEM81 is 1158 bp long and extends from 205,084,360 to 205,085,517 on the reverse strand.[10]

Protein
Schematic illustration of the TMEM81 peptide

The TMEM81 precursor peptide is 255 amino acids long with a predicted molecular weight of 28.5 kDa and pI = 8.92.[11]

The protein contains a helical transmembrane region, an extracellular immunoglobulin domain, and an N-linked glycosylation site. A disulfide bridge is predicted to form between residues Cys104 and Cys156.[11]

Protein composition
Illustration of the human TMEM81 peptide created using Protter[12]

The mature form (signal peptide removed) of TMEM81 has a slightly increased valine and somewhat decreased methionine composition relative to average proteins.[13] TMEM81 also contains three charge runs, each of which are three amino acids long:

ChargeAmino acidsLocation
+Arg-Arg-Lys71–73
-Asp-Asp-Glu131–133
+Lys-Lys-Lys221–223

Secondary structure

The extracellular region of TMEM81 is predicted to be composed of beta sheets while the intracellular region likely assumes an alpha helix conformation. The transmembrane region of TMEM81 is helical.[14] An alignment of mature TMEM81 peptide sequences in H. sapiens, M. musculus and G. gallus was used to predict the secondary structure of TMEM81 using Ali2D.[15]

In predication results given above, blue indicates beta strands while red indicates alpha helices. Color saturation is proportional to the confidence of the predication.

Tertiary structure
TMEM81 predicted tertiary structure (Phyre2)

The tertiary structure of TMEM81 has been predicted using izumo sperm-egg fusion protein 1 as a template. The image on the right depicts a model of residues 19 to 152 with 97.3% confidence with 56% coverage obtained using Phyre2.[16] The red-to-blue color gradation indicates the N- to C-terminus directionality of the structure.

Post-translational modifications

Experimental evidence has been found for an N-glycosylation site located at Asn45 indicating that TMEM81 is a glycoprotein.[14] Several tyrosine residues within TMEM81 have been predicted to undergo sulfation.[17]

Subcellular location

TMEM81 is predicted to be localized to the plasma membrane.[6] However, immunohistochemistry experiments using TMEM81-specific antibodies found localization to intermediate filaments and microfilaments.[18][19]

Expression

Expression in humans

RNA-seq experiments from the GTEx project found that TMEM81 is ubiquitously expressed in humans but shows enhanced expression in the cerebellum and cerebellar hemisphere.[18][20] Other tissues and organs showing somewhat enhanced mRNA expression include the testis and spleen.

Expression in rodents

In mice (M. musculus) and rats (R. norvegicus), TMEM81 shows enhanced expression in the testes and relatively low expression in other tissues.[21][22] Additionally, TMEM81 expression is not localized to the cerebellum in mice.[23]

TMEM81 shows monoallelic expression in both H. sapiens and M. musculus.[24]

Protein expression

In both H. sapiens and M. musculus, TMEM81 is present at a concentration of just under 1 ppm.[25][26] Relative to other proteins, TMEM81 is present at slightly below the median protein concentration level.

Clinical Significance

Methylation changes in TMEM81 are associated with an increased risk of intermittent explosive disorder.[27] Additionally, SNPs located in TMEM81 affect thrombopoiesis, mean platelet volume,[28] and have been implicated in Meniere’s disease.[29]

Cancer

The 1q32.1 region showed copy number gain with a frequency of 68.9% in a study of 46 breast cancers[30] and was gained in a case of extraventricular central neurocytoma.[31] TMEM81 also has been implicated in the development of hepatocellular carcinoma.[32]

Homology

No paralogs of the TMEM81 gene exist in humans. Orthologs of the gene have been found in various lineages of gnathostomes with the most distantly orthologs found among chondrichthyes. TMEM81 orthologs have not been detected among agnatha, lancelets, tunicates, or invertebrates.

Taxonomic nameCommon nameDate of divergence (mya)[33]NCBI Accession #Length (aa)Identity (%) [34]
Homo sapiensHuman0NP_976310255100
Mus musculusMouse89NP_083301.125969.8
Tursiops truncatusDolphin94XP_019773842.125181.4
Loxodonta africanaElephant102XP_023404078.127670.6
Ornithorhynchus anatinusPlatypus180XP_001507541.128154.4
Aptenodytes forsteriPenguin318XP_009271191.126445.7
Notechis scutatusSnake318XP_026532625.124141.9
Melopsittacus undulatusBudgerigar318XP_005140927.229736.9
Microcaecilia unicolorCaecilian352XP_030077474.126638.1
Latimeria chalumnaeCoelacanth414XP_005989300.125434.4
Amphiprion ocellarisClownfish433XP_023128675.125624.9
Rhincodon typusWhale shark465XP_020374416.125729.2

References
  1. GRCh38: Ensembl release 89: ENSG00000174529 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000048174 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. I-TASSER (Iterative Threading ASSEmbly Refinement) server
  6. GeneCards entry on TMEM81
  7. GeneNames entry on TMEM81
  8. BioCyc database entry on TMEM81
  9. ENSEMBL Genome Database entry on TMEM81
  10. ElDorado from Genomatix
  11. NextProt entry on TMEM81
  12. Protter interactive protein visualization tool
  13. Statistical Analysis of Protein Structure
  14. NCBI Nucleotide entry on TMEM81
  15. Ali2D from the MPI Bioinformatics Toolkit
  16. Protein Homology/analogY Recognition Engine V 2.0 (Phyre2)
  17. ExPASy Sulfinator
  18. The Human Protein Atlas Cell entry on TMEM81
  19. Sigma Alderich anti-TMEM81 antibodies
  20. GTEx portal entry on TMEM81
  21. NCBI Gene entry on TMEM81 in M. musculus
  22. NCBI Gene entry on TMEM81 in R. norvegicus
  23. The Human Protein Atlas Brain dataset on TMEM81
  24. dbMAE database results for TMEM81
  25. PaxDB entry on H. sapiens TMEM81
  26. PaxDB entry on H. sapiens TMEM81
  27. Montalvo-Ortiz et al. (2017). Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis. International Journal of Neuropsychopharmacology, 21(1). doi:10.1093/ijnp/pyx087
  28. Shameer et al. (2013). A Genome- and Phenome-Wide Association Study to Identify Genetic Variants Influencing Platelet Count and Volume and their Pleiotropic Effects. Human Genetics, 133(1). doi:10.1007/s00439-013-1355-7
  29. Campbell, C. A. (2010). Identification of a genetic contribution to Meniere’s disease. (Doctoral dissertation, University of Iowa, USA). Retrieved from https://ir.uiowa.edu/etd/2832/
  30. Kawauchi et al. (2010). DNA copy number aberrations associated with aneuploidy and chromosomal instability in breast cancers. Spandidos Publications. doi: 10.3892/or_00000933
  31. Myung et al. (2012). Clinicopathological and genetic characteristics of extraventricular neurocytomas. Neuropathology, 33(2). doi:10,1111/j.1440-1789.2012.01330.x
  32. Chen et al. (2017). Integrative Analysis of Microarray Data to Reveal Regulation Patterns in the Pathogenesis of Hepatocellular Carcinoma. Gut and Liver, 11(1), 112-120. doi:10.5009/gnl16063
  33. Time tree
  34. NCBI Standard Protein BLAST {https://blast.ncbi.nlm.nih.gov/Blast.cgi?PROGRAM=blastp&PAGE_TYPE=BlastSearch&LINK_LOC=blasthome]
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