TMEM81

TMEM81 is also known as HC3107, UNQ2788, KVLA2788,{{cite web |title=TMEM81 |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM81 |website=GeneCards |publisher=Weizmann Institute of Science}} or MGC75217.{{cite web |title=Symbol report for TMEM81 |url=https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:32349 |website=GeneNames |publisher=HUGO Gene Nomenclature Committee (HGNC)}} In humans, TMEM81 is located on chromosomal band 1q32.1 between the genes CNTN2 and RBBP5 on the reverse strand.{{cite web |title=TMEM81 |url=https://biocyc.org/gene?orgid=HUMAN&id=HS16361#tab=showAll |website=BioCyc |publisher=SRI International}} The TMEM81 gene is 1332 base pairs long and encodes one transcript containing a single exon.{{cite web |title=Gene: TMEM81 |url=https://useast.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000174529;r=1:205083129-205084460;t=ENST00000367167 |website=Ensembl Genome Browser |publisher=European Bioinformatics Institute (EMBL-EBI)}}

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.{{cite web |title=Genomes and Annotation: ElDorado |url=https://www.genomatix.de/online_help/help_eldorado/introduction.html |website=Genomatix Software Suite |publisher=Genomatix GmbH |access-date=2022-02-13 |archive-date=2016-06-02 |archive-url=https://web.archive.org/web/20160602041758/https://www.genomatix.de/online_help/help_eldorado/introduction.html |url-status=dead }}

File:Schematic illustration of the TMEM81 peptide.png

The TMEM81 precursor peptide is 255 amino acids long with a predicted molecular weight of 28.5 kDa and pI = 8.92.{{cite web |title=TMEM81 - Proteomics |url=https://www.nextprot.org/entry/Q6P7N7/proteomics |website=neXtProt |publisher=Swiss Institute of Bioinformatics}}

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.

File:Protter TMM81 HUMAN.png

The mature form (signal peptide removed) of TMEM81 has a slightly increased valine and somewhat decreased methionine composition relative to average proteins.{{cite web |title=Statistical Analysis of Protein Structure |url=https://www.ebi.ac.uk/Tools/seqstats/saps/ |publisher=European Bioinformatics Institute (EMBL-EBI)}} TMEM81 also contains three charge runs, each of which are three amino acids long:

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. 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.{{cite web |title=Ali2D |url=https://toolkit.tuebingen.mpg.de/tools/ali2d |website=MPI Bioinformatics Toolkit |publisher=Max Planck Institute for Developmental Biology}}

File:Secondary structure of TMEM81 (predicted by Ali2D).png

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

File:C5f4tA .2.big (1).png

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.{{cite web |title=Phyre2 |url=http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index |website=Protein Homology/analogY Recognition Engine V 2.0 |publisher=Imperial College London}} The red-to-blue color gradation indicates the N- to C-terminus directionality of the structure.

Experimental evidence has been found for an N-glycosylation site located at Asn45 indicating that TMEM81 is a glycoprotein.{{cite journal |title=Homo sapiens transmembrane protein 81 (TMEM81), mRNA |url=https://www.ncbi.nlm.nih.gov/nuccore/NM_203376.2 |website=NCBI Nucleotide Database |date=12 December 2020 |publisher=National Center for Biotechnology Information}} Several tyrosine residues within TMEM81 have been predicted to undergo sulfation.{{cite web |title=Sulfinator |url=https://web.expasy.org/sulfinator/ |website=Expasy |publisher=Swiss Institute of Bioinformatics}}

TMEM81 is predicted to be localized to the plasma membrane. However, immunohistochemistry experiments using TMEM81-specific antibodies found localization to intermediate filaments{{cite web |title=TMEM81 Subcellular |url=https://www.proteinatlas.org/ENSG00000174529-TMEM81/subcellular |website=The Human Protein Atlas |publisher=SciLifeLab, Uppsala University, KTH Royal Institute of Technology}} and microfilaments.{{cite web |title=Anti-TMEM81 antibody produced in rabbit |url=https://www.sigmaaldrich.com/US/en/product/sigma/hpa052515 |website=MilliporeSigma |publisher=Merck Group}}

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.{{cite web |title=Gene Page TMEM81 |url=https://www.gtexportal.org/home/gene/ENSG00000174529 |website=GTEx Portal |publisher=Broad Institute of MIT and Harvard}} Other tissues and organs showing somewhat enhanced mRNA expression include the testis and spleen.

In mice (M. musculus) and rats (R. norvegicus), TMEM81 shows enhanced expression in the testes and relatively low expression in other tissues.{{cite web |title=Tmem81 transmembrane protein 81 [ Mus musculus (house mouse) ] |url=https://www.ncbi.nlm.nih.gov/gene/74626 |website=NCBI Gene Database |publisher=National Center for Biotechnology Information (NCBI)}}{{cite web |title=Tmem81 transmembrane protein 81 [ Rattus norvegicus (Norway rat) ] |url=https://www.ncbi.nlm.nih.gov/gene/?term=tmem81+novegicus |website=NCBI Gene Database |publisher=National Center for Biotechnology Information (NCBI)}} Additionally, TMEM81 expression is not localized to the cerebellum in mice.{{cite web |title=TMEM81 Brain |url=https://www.proteinatlas.org/ENSG00000174529-TMEM81/brain |website=The Human Protein Atlas |publisher=SciLifeLab, Uppsala University, KTH Royal Institute of Technology}}

TMEM81 shows monoallelic expression in both H. sapiens and M. musculus.{{cite web |title=dbMAE |url=https://mae.hms.harvard.edu/sresults.php?gene=tmem81&organism=&tissue=&maestatus=&in_what= |website=dbMAE: the database of autosomal monoallelic expression |publisher=Gimelbrant Lab}}

In both H. sapiens and M. musculus, TMEM81 is present at a concentration of just under 1 ppm.{{cite web |title=TMEM81 Homo sapiens protein|url=https://pax-db.org/protein/4442827 |website=PAXdb: Protein Abundance Database |publisher=Swiss Institute of Bioinformatics, University of Zurich}}{{cite web |title=Tmem81 Mus musculus protein |url=https://pax-db.org/protein/5037032 |website=PAXdb: Protein Abundance Database |publisher=Swiss Institute of Bioinformatics, University of Zurich}} Relative to other proteins, TMEM81 is present at slightly below the median protein concentration level.

Methylation changes in TMEM81 are associated with an increased risk of intermittent explosive disorder.{{cite journal | vauthors = Montalvo-Ortiz JL, Zhang H, Chen C, Liu C, Coccaro EF | title = Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis | journal = The International Journal of Neuropsychopharmacology | volume = 21 | issue = 1 | pages = 12–20 | date = January 2018 | pmid = 29106553 | pmc = 5789263 | doi = 10.1093/ijnp/pyx087 }} Additionally, SNPs located in TMEM81 affect thrombopoiesis, mean platelet volume,{{cite journal | vauthors = Shameer K, Denny JC, Ding K, Jouni H, Crosslin DR, de Andrade M, Chute CG, Peissig P, Pacheco JA, Li R, Bastarache L, Kho AN, Ritchie MD, Masys DR, Chisholm RL, Larson EB, McCarty CA, Roden DM, Jarvik GP, Kullo IJ | display-authors = 6 | title = A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects | journal = Human Genetics | volume = 133 | issue = 1 | pages = 95–109 | date = January 2014 | pmid = 24026423 | pmc = 3880605 | doi = 10.1007/s00439-013-1355-7 }} and have been implicated in Meniere’s disease.{{cite thesis | vauthors = Campbell CA | date = 2010 | title = \Identification of a genetic contribution to Meniere's disease. | degree= Ph.D. | publisher = University of Iowa, USA) | url = https://iro.uiowa.edu/esploro/outputs/doctoral/Identification-of-a-genetic-contribution-to/9983776996202771 }}

The 1q32.1 region showed copy number gain with a frequency of 68.9% in a study of 46 breast cancers{{cite journal | vauthors = Kawauchi S, Furuya T, Ikemoto K, Nakao M, Yamamoto S, Oka M, Sasaki K | title = DNA copy number aberrations associated with aneuploidy and chromosomal instability in breast cancers | journal = Oncology Reports | volume = 24 | issue = 4 | pages = 875–83 | date = October 2010 | pmid = 20811667 | doi = 10.3892/or.2010.875 | doi-access = free }} and was gained in a case of extraventricular central neurocytoma.{{cite journal | vauthors = Myung JK, Cho HJ, Park CK, Chung CK, Choi SH, Kim SK, Park SH | title = Clinicopathological and genetic characteristics of extraventricular neurocytomas | journal = Neuropathology | volume = 33 | issue = 2 | pages = 111–121 | date = April 2013 | pmid = 22672632 | doi = 10.1111/j.1440-1789.2012.01330.x | s2cid = 2024518 | doi-access = free }} TMEM81 also has been implicated in the development of hepatocellular carcinoma.{{cite journal | vauthors = Chen J, Qian Z, Li F, Li J, Lu Y | title = Integrative Analysis of Microarray Data to Reveal Regulation Patterns in the Pathogenesis of Hepatocellular Carcinoma | journal = Gut and Liver | volume = 11 | issue = 1 | pages = 112–120 | date = January 2017 | pmid = 27458175 | pmc = 5221868 | doi = 10.5009/gnl16063 }}

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.

{{Reflist}}