TMEM221

Transmembrane protein 221 (TMEM221) is a protein that in humans is encoded by the TMEM221 gene.[5] The function of TMEM221 is currently not well understood.

TMEM221
Identifiers
AliasesTMEM221, transmembrane protein 221
External IDsMGI: 3525074 HomoloGene: 110174 GeneCards: TMEM221
Gene location (Human)
Chr.Chromosome 19 (human)[1]
Band19p13.11Start17,435,509 bp[1]
End17,448,668 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

100130519

434325

Ensembl

ENSG00000188051

ENSMUSG00000043664

UniProt

A6NGB7

Q8K071

RefSeq (mRNA)

NM_001190844

NM_001100462

RefSeq (protein)

NP_001177773

NP_001093932

Location (UCSC)Chr 19: 17.44 – 17.45 MbChr 8: 71.55 – 71.56 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

General properties

TMEM221 is also known as Putative Transmembrane Protein ENSP00000342162.[6] 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.[5] 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.[7]

Promoter

The predicted promoter region (GXP_1485843) is 2016 base pairs long and extends into the beginning of the second exon of TMEM221.[8] The most abundant and highly predicted transcription factors predicted to bind to the promoter are outlined in the table below.  

Transcription Factor Detailed Matrix Information Anchor Base Matrix Similarity Sequence
BRNF Brn POU domain factors 11 0.905 caaccatTAATctacttct
KLFS Krueppel like transcription factor 45 0.939 gggggaatggGGAGtggct
LHXF Lim homeodomain factors 156 0.931 taaaatgaTTAAttttatgttat
HOXF Paralog hox genes 1-8 from the four hox clusters A, B, C, D 210 0.899 gcgaaTAATttgggggacc
CTCF CTCF and BORIS gene family, transcriptional regulators with 11 highly conserved zinc finger domains 256 0.813 cgttgcttcctctaggaGGCTagggag
PBXC Pre B-cell leukemia homeobox 3 403 1.000 agcctgagTGACagagc
NKRF Nuclear factor-kappaB repressing factor 590 0.854 aacTCCTgggc
LEFF T-cell specific HMG-box transcription factor 7 701 0.879 actccatCAAAaaaaaa
CEBP Ccaat/Enhancer Binding Protein 744 0.941 gcagtggtGCAAtct
HNFP Histone nuclear factor P 763 0.843 ggCGGAggttgcagtgagc
CART Cart-1 (cartilage homeoprotein 1) 854 0.862 cgggcTAATtttttttttttt
TF2B RNA polymerase II transcription factor II B 987 1.000 ccgCGCC
CAAT CCAAT binding factor 1229 0.926 ctggCCAAtatggtg
VTBP Vertebrate TATA binding protein factor 1342 0.852 tgtttTAAAccacaata
PLAG Pleomorphic adenoma gene 1419 0.844 ctgtGGGGttcccgcgatccagt
NDPK Nucleoside diphosphate kinase 1447 0.910 gcAGGGcggggaggccc
E2FF E2F-myc activator/cell cycle regulator 1471 0.989 gcgggGCGGggcctggc
ZF5F ZF5 POZ domain zinc finger 1504 0.957 gaggggGCGCccgcg
ZF5F 1505 0.957 ccgcggGCGCcccct
ZTRE Zinc transcriptional regulatory element 1525 0.988 ccgGGAGggaggagaaa

Expression

Expression profile of TMEM221.[5]

TMEM221 is highly expressed relative to other human genes in nearly every tissue type, suggesting it could potentially be a housekeeping gene.[9] It is shown consistently to be most highly expressed in the brain, adrenal gland, and ovaries.[10] Conditional expression demonstrates decreased expression of TMEM221 in ovarian cancer, lymphomas, and bone cancer.[11][12][13][14]

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.[5]

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.[7]

Protein

General properties

TMEM221 transmembrane domains.[15]
TMEM221 transmembrane helices.

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.[16] TMEM221 has a predicted molecular weight of 30 kDa and is slightly basic with a predicted isoelectric point of 8.6.[17]

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.[18]

Domains and Motifs

TMEM221 has two conserved motifs, Jiraiya and DUF5408.[19] 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.[20] The DUF5408 motif is not yet characterized.

Structure

Tertiary structure of TMEM221.[21]

TMEM221 protein is predicted to be composed of approximately 58% random coil, 20% alpha helix, and 22% extended strand.[22][23] 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.[24]

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.[25]

Signal peptide

TMEM221 has a predicted signal peptide cleavage site between bases 24 and 25.[26][27]

Post-translational modifications

TMEM221 conceptual translation.

The only lipid modification TMEM221 has is one palmitoylation site, indicating that its trafficking may not be highly regulated.[28] There is one predicted glycation site.[29] There is one NES signal which is expected as the protein is expected to be located in the cytoplasm, among other locations.[30][31] O-glycosylation is predicted at three sites that are likely important for protein stability and function.[32] There are many possible phosphorylation sites, some with multiple possible kinases, that are likely important for protein activation.[33] There is one SUMOylation site that would aid in nuclear-cytosolic transport.[34]

Homology/evolution

Paralogs

TMEM221 has one predicted paralog, hCG2038292.[6] This protein is mostly highly conserved through the Jiraiya sequence. This diverged approximately 400 million years ago.

Orthologs

Phylogenetic tree of TMEM221.

TMEM221 is conserved throughout vertebrates but not in invertebrates, plants, or any other organisms. The most distant identified ortholog is the live shark sucker.[35]

Genus and Species Common Name Taxonomic Group DoD (mya) Accession Number Sequence Length (AA) Percent Identity
Homo sapiens Human Mammal, Primate 0 NP_001177773.1 291 100%
Pan troglodytes Chimpanzee Mammal, Primate 7 XP_016790933.2 291 98%
Papio anubis Olive Baboon Mammal, Primate 29 XP_003919243.1 290 96%
Cricetulus griseus Chinese Hamster Mammal, Rodentia 89 XP_027250594.1 291 72%
Ursus arctos Grizzly Bear Mammal, Carnivora 96 XP_026356267.1 291 87%
Hipposideros armiger Great Roundleaf Bat Mammal, Chiroptera 96 XP_019497376.1 291 85%
Trichechus manatus latirostris West Indian Manatee Mammal, Sirenia 105 XP_004384461.1 291 86%
Phascolarctos cinereus Koala Marsupial 159 XP_020864777.1 288 48%
Crocodylus porosus Saltwater Crocodile Reptile 312 XP_019393978.1 233 38%
Egretta garzetta Little Egret Bird 312 XP_009641067.1 209 32%
Podarcis muralis Common Wall Lizard Reptile 318 XP_028569471.1 305 43%
Chelonia mydas Green Sea Turtle Reptile 318 XP_027689962.1 280 33%
Phaethon lepturus White-tailed Tropicbird Bird 318 XP_010280379.1 200 30%
Python bivittatus Burmese Python Reptile 318 XP_025027154.1 232 30%
Antrostomus carolinensis Chuck-will’s-widow Bird 318 XP_010164009.2 207 23%
Xenopus tropicalis Western Clawed Frog Amphibian 352 XP_004911082.1 306 37%
Xenopus laevis African Clawed Frog Amphibian 352 NP_001182024.1 306 37%
Danio rerio Zebrafish Fish 433 XP_003201087.1 287 37%
Salmo trutto Brown Trout Fish 433 XP_029562717.1 304 34%
Lepisosteus osculatus Spotted Gard Fish 433 XP_015221220.1 170 17%
Echeneis naucrates Live Shark Sucker Fish 433 XP_029356055.1 312 34%

Rate of Evolution

Rate of divergence of TMEM221 as compared to fibrinogen and cytochrome C.

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.[36] These are all predicted to play an important role in taste cell function.[37]

Clinical significance

Disease association

A human disease known to be associated with TMEM221 is amoebiasis, a digestive infection caused by the amoeba Entamoeba histolytica.[6][38] The gene is also shown to be less expressed in a multitude of cancers including ovarian cancer, lymphoma, and bone cancer among others.[12][13][14]

Mutations

There were many potential sites for SNPs in the coding sequence of TMEM221.[39] 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 number
13 Frame Shift/Nonsense 1 A → - M → stop rs758599058
33 Nonsense 1 C → T Q → stop rs1304244986
44 Frame Shift 3 G → - L → C rs1425689981
103 Frame Shift 3 G → - P → L rs1402509177
110 Nonsense

Frameshift

Missense

Missense

Nonsense

3

3

2

2

2

G → A

G → -

G → T

G → C

G → A

W → stop

W → C

W → L

W → S

W → stop

rs1448161781


rs541140024

112 Missense 2 T → C L → P rs987960379
136 Frame Shift 3 A → - A → H rs1004328462
194 Missense 1

1

G → C

G → A

D → H

D → N

rs990835413
209 Nonsense 1 C → T Q → stop rs906917531
228 Frame Shift 1 G → - D → T rs1434673805
235 Frame Shift 3 + C T → H rs149217587
272 Missense

Nonsense

1 G → A

G → T

E → K

E → stop

rs186899872

References

  1. GRCh38: Ensembl release 89: ENSG00000188051 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000043664 - 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. "Homo sapiens transmembrane protein 221 (TMEM221), mRNA". 2019-09-12. Cite journal requires |journal= (help)
  6. "TMEM221 Gene - GeneCards | TM221 Protein | TM221 Antibody". www.genecards.org. Retrieved 2020-05-03.
  7. "Human hg38 chr19:17,435,509-17,448,668 UCSC Genome Browser v397". genome.ucsc.edu. Retrieved 2020-05-03.
  8. Genomatix. http://www.genomatix.de/?s=2d8a13e175653babaccb07b76acc8cd2
  9. "GDS424 / 51886_at". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  10. Gene NCBI (National Center for Biotechnology Information) https://www.ncbi.nlm.nih.gov/gene/100130519
  11. "GDS5816 / ILMN_3261382". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  12. "GDS3754 / 239128_at". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  13. "GDS5375 / ILMN_3261382". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  14. "GDS5367 / ILMN_3261382". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  15. "SOSUI: submit protein sequences". harrier.nagahama-i-bio.ac.jp. Retrieved 2020-05-03.
  16. NCBI Protein. https://www.ncbi.nlm.nih.gov/protein/300068980
  17. ExPASy Compute pI/mW tool. https://web.expasy.org/compute_pi/
  18. SAPS (Stastical Analysis of Protein Sequences). https://www.ebi.ac.uk/Tools/seqstats/saps/
  19. GenomeNet Motif Search. https://www.genome.jp/tools/motif/
  20. Aramaki, T., Sasai, N., Yakura, R., Yoshiki, S. (2010). Jiraiya Attenuates BMP Signaling by Interfering with Type II BMP Receptors in Neuroectodermal Patterning. Developmental Cell, 19(4), 547-561. https://doi.org/10.1016/j.devcel.2010.09.001
  21. Nucleotide NCBI (National Center for Biotechnology Information) https://www.ncbi.nlm.nih.gov/nuccore/NM_001190844.2
  22. CFSSP (Chou and Fasman Secondary Structure Prediction). http://www.biogem.org/tool/chou-fasman/
  23. GOR4. https://npsa-prabi.ibcp.fr/cgi-bin/secpred_gor4.pl
  24. DISULFIND. http://disulfind.dsi.unifi.it/monitor.php?query=v5DhKu
  25. PSORT II. https://psort.hgc.jp/form2.html
  26. LipoP. http://www.cbs.dtu.dk/services/LipoP/
  27. ProP. http://www.cbs.dtu.dk/services/ProP/
  28. The Cuckoo Workgroup. Prediction of Palmitoylation Sites. http://csspalm.biocuckoo.org/index.php
  29. NetGlycate. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5E9CF22B000010DD7A4E9449&wait=20
  30. NetNES. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5E9CF2F50000064ECAE3DE03&wait=20
  31. Phobius. http://phobius.sbc.su.se/cgi-bin/predict.pl
  32. NetOGlyc. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5E9CF3370000064E3DFD9AC3&wait=20
  33. NetPhos. http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5E9CF3BA000010DD71873F80&wait=20
  34. The Cuckoo Group. Prediction of SUMOylation Sites. http://sumosp.biocuckoo.org/showResult.php
  35. Blast NCBI (National Center for Biotechnology Information) https://blast.ncbi.nlm.nih.gov/Blast.cgi
  36. STRING. https://string-db.org/cgi/input.pl?sessionId=nXvhj5eKuvP5&input_page_show_search=on
  37. Ren, W., Aihara, E., Lei, W. et al. Transcriptome analyses of taste organoids reveal multiple pathways involved in taste cell generation. Sci Rep 7, 4004 (2017). https://doi.org/10.1038/s41598-017-04099-5
  38. CDC Amebiasis (Center for Disease Control and Prevention) https://www.cdc.gov/parasites/amebiasis/general-info.html
  39. Gene SNP. https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=100130519
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