TMEM221

Last updated
TMEM221
Identifiers
Aliases TMEM221 , transmembrane protein 221
External IDs MGI: 3525074 HomoloGene: 110174 GeneCards: TMEM221
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001190844

NM_001100462

RefSeq (protein)

NP_001177773

NP_001093932

Location (UCSC) Chr 19: 17.44 – 17.45 Mb Chr 8: 72.01 – 72.01 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Contents

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 to bind to the promoter are outlined in the table below.  

Transcription FactorDetailed Matrix InformationAnchor BaseMatrix SimilaritySequence
BRNFBrn POU domain factors110.905caaccatTAATctacttct
KLFSKrueppel like transcription factor450.939gggggaatggGGAGtggct
LHXFLim homeodomain factors1560.931taaaatgaTTAAttttatgttat
HOXFParalog hox genes 1-8 from the four hox clusters A, B, C, D2100.899gcgaaTAATttgggggacc
CTCFCTCF and BORIS gene family, transcriptional regulators with 11 highly conserved zinc finger domains2560.813cgttgcttcctctaggaGGCTagggag
PBXCPre B-cell leukemia homeobox 34031.000agcctgagTGACagagc
NKRFNuclear factor-kappaB repressing factor5900.854aacTCCTgggc
LEFFT-cell specific HMG-box transcription factor 77010.879actccatCAAAaaaaaa
CEBPCcaat/Enhancer Binding Protein7440.941gcagtggtGCAAtct
HNFPHistone nuclear factor P7630.843ggCGGAggttgcagtgagc
CARTCart-1 (cartilage homeoprotein 1)8540.862cgggcTAATtttttttttttt
TF2BRNA polymerase II transcription factor II B9871.000ccgCGCC
CAATCCAAT binding factor12290.926ctggCCAAtatggtg
VTBPVertebrate TATA binding protein factor13420.852tgtttTAAAccacaata
PLAGPleomorphic adenoma gene14190.844ctgtGGGGttcccgcgatccagt
NDPKNucleoside diphosphate kinase14470.910gcAGGGcggggaggccc
E2FFE2F-myc activator/cell cycle regulator14710.989gcgggGCGGggcctggc
ZF5FZF5 POZ domain zinc finger15040.957gaggggGCGCccgcg
ZF5F15050.957ccgcggGCGCcccct
ZTREZinc transcriptional regulatory element15250.988ccgGGAGggaggagaaa

Expression

Expression profile of TMEM221. Tmem221expression.png
Expression profile of TMEM221.

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. TMEM221 TM Domains.png
TMEM221 transmembrane domains.
TMEM221 transmembrane helices. TMEM221 TM helices.png
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. Tmem221 tertiary structure.png
Tertiary structure of TMEM221.

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. TMEM221 conceptual translation.png
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 Phylogenetic Tree.png
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 SpeciesCommon NameTaxonomic GroupDoD (mya)Accession NumberSequence Length (AA)Percent Identity
Homo 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

Rate of divergence of TMEM221 as compared to fibrinogen and cytochrome C. Divergence rate of TMEM221.png
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 ProteinMutation TypeCodon PositionChange in Nucleic AcidChange in Amino AcidRs number
13Frame Shift/Nonsense1A → -M → stoprs758599058
33Nonsense1C → TQ → stoprs1304244986
44Frame Shift3G → -L → Crs1425689981
103Frame Shift3G → -P → Lrs1402509177
110Nonsense

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

112Missense2T → CL → Prs987960379
136Frame Shift3A → -A → Hrs1004328462
194Missense1

1

G → C

G → A

D → H

D → N

rs990835413
209Nonsense1C → TQ → stoprs906917531
228Frame Shift1G → -D → Trs1434673805
235Frame Shift3+ CT → Hrs149217587
272Missense

Nonsense

1G → A

G → T

E → K

E → stop

rs186899872

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