Transmembrane protein 221 (TMEM221) is a protein that in humans is encoded by the TMEM221 gene. The function of TMEM221 is currently not well understood.
Gene
General properties TMEM221 is also known as Putative Transmembrane Protein ENSP00000342162. The TMEM221 gene is 13,159 base pairs long, contains three exons, and is located on the short arm of chromosome 19 at 19p13.11 in humans. It spans from 17,435,509 to 17,448,668 on the minus strand. It is flanked by MVB12A upstream, and by AC010319.5 and NXNL1 downstream.
Promoter The predicted promoter region (GXP_1485843) is 2016 base pairs long and extends into the beginning of the second exon of TMEM221.Genomatix. http://www.genomatix.de/?s=2d8a13e175653babaccb07b76acc8cd2 The most abundant and highly predicted transcription factors to bind to the promoter are outlined in the table below. Transcription factor Detailed matrix information Anchor base Matrix similarity SequenceBRNFBrn POU domain factors110.905caaccatTAATctacttctKLFSKrueppel like transcription factor450.939gggggaatggGGAGtggctLHXFLim homeodomain factors1560.931taaaatgaTTAAttttatgttatHOXFParalog hox genes 1-8 from the four hox clusters A, B, C, D2100.899gcgaaTAATttgggggaccCTCFCTCF and BORIS gene family, transcriptional regulators with 11 highly conserved zinc finger domains2560.813cgttgcttcctctaggaGGCTagggagPBXCPre B-cell leukemia homeobox 34031.000agcctgagTGACagagcNKRFNuclear factor-kappaB repressing factor5900.854aacTCCTgggcLEFFT-cell specific HMG-box transcription factor 77010.879actccatCAAAaaaaaaCEBPCcaat/Enhancer Binding Protein7440.941gcagtggtGCAAtctHNFPHistone nuclear factor P7630.843ggCGGAggttgcagtgagcCARTCart-1 (cartilage homeoprotein 1)8540.862cgggcTAATttttttttttttTF2BRNA polymerase II transcription factor II B9871.000ccgCGCCCAATCCAAT binding factor12290.926ctggCCAAtatggtgVTBPVertebrate TATA binding protein factor13420.852tgtttTAAAccacaataPLAGPleomorphic adenoma gene14190.844ctgtGGGGttcccgcgatccagtNDPKNucleoside diphosphate kinase14470.910gcAGGGcggggaggcccE2FFE2F-myc activator/cell cycle regulator14710.989gcgggGCGGggcctggcZF5FZF5 POZ domain zinc finger15040.957gaggggGCGCccgcgZF5F15050.957ccgcggGCGCcccctZTREZinc transcriptional regulatory element15250.988ccgGGAGggaggagaaa
Expression
TMEM221 is highly expressed relative to other human genes in nearly every tissue type, suggesting it could potentially be a housekeeping gene. It is shown consistently to be most highly expressed in the brain, adrenal gland, and ovaries.Gene NCBI (National Center for Biotechnology Information) https://www.ncbi.nlm.nih.gov/gene/100130519 Conditional expression demonstrates decreased expression of TMEM221 in ovarian cancer, lymphomas, and bone cancer.
mRNA The longest transcript of TMEM221 is 2,301 base pairs longs. It has one X1 isoform that is 1,547 base pairs long and contains one exon.
Transcript level regulation The mRNA structure of TMEM221 is predicted to have stem loop formation important for protein recognition and stability. There is one splice enhancer site with two DNAse hypersensitivity sites and bindings sites for transcription factors including CTCF, FOS, NFYB, and NFYA.
Protein
General properties
The TMEM221 protein is 291 amino acids long and contains four transmembrane domains. The protein of the X1 variant is 232 amino acids long and contains one transmembrane domain.NCBI Protein. https://www.ncbi.nlm.nih.gov/protein/300068980 TMEM221 has a predicted molecular weight of 30 kDa and is slightly basic with a predicted isoelectric point of 8.6.ExPASy Compute pI/mW tool. https://web.expasy.org/compute_pi/
Composition TMEM221 has a significantly higher composition of leucine, alanine, and glycine as compared to other human proteins. It also has a significantly lower composition of asparagine and isoleucine. It has no high scoring charge clusters or charged segments.SAPS (Stastitical Analysis of Protein Sequences). https://www.ebi.ac.uk/Tools/seqstats/saps/
Domains and Motifs TMEM221 has two conserved motifs, Jiraiya and DUF5408.GenomeNet Motif Search. https://www.genome.jp/tools/motif/ The Jiraiya motif was found in all orthologs and composes the three latter transmembrane regions. Jiraiya is reported to be a factor in attenuation of bone morphogenetic protein (BMP) signaling. The DUF5408 motif is not yet characterized.
Structure
TMEM221 protein is predicted to be composed of approximately 58% random coil, 20% alpha helix, and 22% extended strand.CFSSP (Chou and Fasman Secondary Structure Prediction). http://www.biogem.org/tool/chou-fasman/GOR4. https://npsa-prabi.ibcp.fr/cgi-bin/secpred_gor4.pl The tertiary structure is predicted to have three disulfide bridges between conserved cysteines that are in the non-cytoplasmic regions as well as one crossing between the non-cytoplasmic region and the second transmembrane region.DISULFIND. http://disulfind.dsi.unifi.it/monitor.php?query=v5DhKu
Subcellular location TMEM221 is predicted to be mostly localized to the endoplasmic reticulum, but also distributed throughout the mitochondria, vacuolar, plasma membrane, and extracellular space.PSORT II. https://psort.hgc.jp/form2.html
Signal peptide TMEM221 has a predicted signal peptide cleavage site between bases 24 and 25.LipoP. http://www.cbs.dtu.dk/services/LipoP/ProP. http://www.cbs.dtu.dk/services/ProP/
Post-translational modifications
The only lipid modification TMEM221 has is one palmitoylation site, indicating that its trafficking may not be highly regulated.The Cuckoo Workgroup. Prediction of Palmitoylation Sites. http://csspalm.biocuckoo.org/index.php There is one predicted glycation site.NetGlycate. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5E9CF22B000010DD7A4E9449&wait=20 There is one NES signal which is expected as the protein is expected to be located in the cytoplasm, among other locations.NetNES. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5E9CF2F50000064ECAE3DE03&wait=20Phobius. http://phobius.sbc.su.se/cgi-bin/predict.pl O-glycosylation is predicted at three sites that are likely important for protein stability and function.NetOGlyc. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5E9CF3370000064E3DFD9AC3&wait=20 There are many possible phosphorylation sites, some with multiple possible kinases, that are likely important for protein activation.NetPhos. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5E9CF3BA000010DD71873F80&wait=20 There is one SUMOylation site that would aid in nuclear-cytosolic transport.The Cuckoo Group. Prediction of SUMOylation Sites. http://sumosp.biocuckoo.org/showResult.php
Homology/evolution
Paralogs TMEM221 has one predicted paralog, hCG2038292. This protein is mostly highly conserved through the Jiraiya sequence. This diverged approximately 400 million years ago.
Orthologs
TMEM221 is conserved throughout vertebrates but not in invertebrates, plants, or any other organisms. The most distant identified ortholog is the live shark sucker.Blast NCBI (National Center for Biotechnology Information) https://blast.ncbi.nlm.nih.gov/Blast.cgi Genus and species Common name Taxonomic group DoD (mya) Accession number Sequence length (AA) Percent identityHomo sapiensHumanMammal, Primate0NP_001177773.1291100%Pan troglodytesChimpanzeeMammal, Primate7XP_016790933.229198%Papio anubisOlive BaboonMammal, Primate29XP_003919243.129096%Cricetulus griseusChinese HamsterMammal, Rodentia89XP_027250594.129172%Ursus arctosGrizzly BearMammal, Carnivora96XP_026356267.129187%Hipposideros armigerGreat Roundleaf BatMammal, Chiroptera96XP_019497376.129185%Trichechus manatus latirostrisWest Indian ManateeMammal, Sirenia105XP_004384461.129186%Phascolarctos cinereusKoalaMarsupial159XP_020864777.128848%Crocodylus porosusSaltwater CrocodileReptile312XP_019393978.123338%Egretta garzettaLittle EgretBird312XP_009641067.120932%Podarcis muralisCommon Wall LizardReptile318XP_028569471.130543%Chelonia mydasGreen Sea TurtleReptile318XP_027689962.128033%Phaethon lepturusWhite-tailed TropicbirdBird318XP_010280379.120030%Python bivittatusBurmese PythonReptile318XP_025027154.123230%Antrostomus carolinensisChuck-will's-widowBird318XP_010164009.220723%Xenopus tropicalisWestern Clawed FrogAmphibian352XP_004911082.130637%Xenopus laevisAfrican Clawed FrogAmphibian352NP_001182024.130637%Danio rerioZebrafishFish433XP_003201087.128737%Salmo truttoBrown TroutFish433XP_029562717.130434%Lepisosteus osculatusSpotted GardFish433XP_015221220.117017%Echeneis naucratesLive Shark SuckerFish433XP_029356055.131234%
Rate of Evolution
TMEM221 is a rapidly evolving gene with a rate of divergence faster than cytochrome C, a slowly evolving gene, and fibrinogen, a rapidly evolving gene.
Function/biochemistry
Interacting proteins TMEM221 has been shown to interact with GPR137C, TMEM211, OVOL3, TMEM132E, TMEM171, TMEM150C, GPR162, TMC5, and BAI2.STRING. https://string-db.org/cgi/input.pl?sessionId=nXvhj5eKuvP5&input_page_show_search=on These are all predicted to play an important role in taste cell function.
Clinical significance
Disease association A human disease known to be associated with TMEM221 is amoebiasis, a digestive infection caused by the amoeba Entamoeba histolytica.CDC Amebiasis (Center for Disease Control and Prevention) https://www.cdc.gov/parasites/amebiasis/general-info.html The gene is also shown to be less expressed in a multitude of cancers including ovarian cancer, lymphoma, and bone cancer among others.
Mutations There were many potential sites for SNPs in the coding sequence of TMEM221.Gene SNP. https://www.ncbi.nlm.nih.gov/variation/view/?q=100130519[geneid] Notably, W110 has five potential SNPs in its second and third codon positions. There are many other SNPs identified in other conserved amino acids, but these resulted in silent mutations. Position in protein Mutation type Codon position Change in nucleic acid Change in amino acid Rs number13Frame Shift/Nonsense1A → -M → stoprs75859905833Nonsense1C → TQ → stoprs130424498644Frame Shift3G → -L → Crs1425689981103Frame Shift3G → -P → Lrs1402509177110Nonsense
Frameshift
Missense
Missense
Nonsense3
3
2
2
2G → A
G → -
G → T
G → C
G → AW → stop
W → C
W → L
W → S
W → stoprs1448161781
rs541140024112Missense2T → CL → Prs987960379136Frame Shift3A → -A → Hrs1004328462194Missense1
1G → C
G → AD → H
D → Nrs990835413209Nonsense1C → TQ → stoprs906917531228Frame Shift1G → -D → Trs1434673805235Frame Shift3+ CT → Hrs149217587272Missense
Nonsense1G → A
G → TE → K
E → stoprs186899872
References