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TMEM101

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TMEM101
Identifiers
AliasesTMEM101, transmembrane protein 101
External IDsMGI: 1923797; HomoloGene: 12649; GeneCards: TMEM101; OMA:TMEM101 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

84336

76547

Ensembl

ENSG00000091947

ENSMUSG00000020921

UniProt

Q96IK0

Q91VP7

RefSeq (mRNA)

NM_001304813
NM_001304814
NM_032376

NM_029649

RefSeq (protein)

NP_001291742
NP_001291743
NP_115752

NP_083925

Location (UCSC)Chr 17: 44.01 – 44.02 MbChr 11: 102.04 – 102.05 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Transmembrane protein 101 (TMEM101) is a protein that in humans is encoded by the TMEM101 gene.[5] The TMEM101 protein has been demonstrated to activate the NF-κB signaling pathway.[6] High levels of expression of TMEM101 have been linked to breast cancer.[7]

Gene

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Aliases

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Known aliases of TMEM101 include Putative NF-Kappa-B-Activating Protein 130, FLJ23987, and MGC4251.[8]

Location

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TMEM101 is located on the minus strand of the long arm of human chromosome 17 at the locus 17q21.31.[5] The gene is 12,758 bp long, and it ranges from position 44,011,188 to position 44,023,946 on chromosome 17.[5] TMEM101 is located between the genes NAGS and LSM12.[5]

Transcript Variants

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NCBI RefSeq contains five mRNA transcript variants for TMEM101.[5] Transcript variants 1, 2, and 3 have been found experimentally, while transcript variants X1 and X2 have been predicted computationally.[5] The last three exons of all five transcript variants are identical. The second exon is identical in transcript variants 2 and 3. The first exon of variant X1 and the second exon of variant X2 are nearly identical to the second exon of variants 2 and 3, but both contain an additional segment of bases at the 3’ end of this exon, and the first exon of variant X1 has 6 extra bases on the 5’ end. The first exon differs considerably in length between variants 2, X2, and 3.

Transcript variants of TMEM101 mRNA
Name Accession Number Number of Exons Size (bp)
Transcript Variant 1 NM_032376.4 4 1525
Transcript Variant X1 XM_024451006.1 4 1602
Transcript Variant 2 NM_001304813.2 5 1726
Transcript Variant X2 XM_011525353.2 5 4604
Transcript Variant 3 NM_001304814.2 5 1759

Protein

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Homo sapiens TMEM101 conceptual translation

Isoforms

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There are two known isoforms of the TMEM101 protein. Isoform a is encoded by transcript variant 1, while isoform b is encoded by transcript variants 2 and 3.[5] Transcript variants X1 and X2 are also predicted to encode isoform b. Isoform b lacks the first 58 amino acids following the N-terminus of isoform a, but the remaining 199 amino acids are identical to isoform a.

Isoforms of the TMEM101 protein
Name Accession Number Size (aa) Predicted molecular weight (kDa)[9]
Isoform a NP_115752.1 257 29
Isoform b NP_001291742.1 199 22

Protein Characteristics

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Amino acid compositional analysis (SAPS)

Isoform a of the TMEM101 protein has a predicted molecular weight of about 29 kDa and a theoretical isoelectric point of about 9.6.[9] In terms of amino acid composition, TMEM101 is relatively rich in the hydrophobic amino acids leucine and tyrosine, and relatively poor in the hydrophilic amino acids asparagine and threonine.[10] It is also relatively poor in the sum of the two negatively charged amino acids, aspartic acid and glutamic acid.[10]

Transmembrane Domains

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Isoform a of the TMEM101 protein contains 8 transmembrane domains.[11]

Schematic illustration of transmembrane domains and predicted post-translational modification sites
Transmembrane domains of the TMEM101 protein (isoform a)
Transmembrane Domain Amino Acids
1 21-40
2 52-72
3 77-97
4 110-130
5 139-159
6 182-202
7 206-226
8 233-257

Secondary Structure

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Predicted secondary structure (Phyre2)

The Ali2D, I-TASSER, and Phyre2 models all predict that the secondary structure of TMEM101 is predominately composed of alpha helices.[12][13][14] The Phyre2 prediction is presented in the figure to the right.

Tertiary Structure

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Predicted tertiary structure (I-TASSER)

The I-TASSER highest confidence model for the predicted tertiary structure for the TMEM101 protein resembles the structure of a polytopic transmembrane alpha-helical protein.[13]

Post-translational Modifications

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Acetylation

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The lysine at position 4 in the TMEM101 protein is predicted to be acetylated by the EP300 acetyltransferase enzyme.[15]

Phosphorylation

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There are five predicted phosphorylation sites located outside of transmembrane domains on the cytoplasmic side of the TMEM101 protein, which are listed in the table below.[16]

Predicted phosphorylation sites in the TMEM101 protein
Position Amino Acid
98 Tyrosine
101 Tyrosine
162 Serine
169 Tyrosine
228 Threonine

Subcellular Localization

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Immunofluorescent staining experiments have detected the TMEM101 protein in the plasma membrane and the nucleoplasm.[17]

Regulation and Expression

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Promoters

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The Genomatix Gene2Promoter tool lists 7 promoter regions for the Homo sapiens TMEM101 gene.[18] The promoter that is supported by the greatest number of mRNA transcripts is 1525 bp long and spans the base pairs 44014913–44016437 on the negative strand of human chromosome 17. This promoter overlaps the start of transcription of mRNA transcript variant 1.

Alignment of promoters with the TMEM101 gene and mRNA transcript variants
Promoters for the TMEM101 gene (predicted by Genomatix Gene2Promoter)
Number Promoter ID Start position End position Length (bp) Number of supporting transcripts
1 GXP_8985856 44014913 44016437 1525 5
2 GXP_9511469 44015003 44016042 1040 1
3 GXP_8985857 44026007 44027046 1040 1
4 GXP_6035198 44023907 44024946 1040 1
5 GXP_6035197 44019403 44020447 1045 3
6 GXP_4414506 44023067 44024152 1085 4
7 GXP_44546 44021160 44022199 1040 1

Transcription Factors

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The following table presents a selected list of transcription factors that are predicted by the Genomatix MatInspector tool to bind to the GXP_8985856 promoter.[19]

Predicted transcription factor binding sites
Selected transcription factors predicted to bind to the TMEM101 promoter (predicted by Genomatix MatInspector)
Transcription Factor Description
TFIIB Transcription factor II B
FOXP1 Forkhead box protein P1
ZNF384 Zinc finger protein 384
ZNF300 KRAB-containing zinc finger protein 300
MZF1 Myeloid zinc finger protein MZF1
SIX4 Sine oculis homeobox homolog 4
ETV4 ETS translocation variant 4
ELK1 Elk-1
HIC1 Hypermethylated in cancer 1
ZNF217 Zinc finger protein 217
LHX6 LIM homeobox 6

Expression

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TMEM101 expression levels by tissue (Human Protein Atlas)

Tissue Specificity

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According to RNA-Seq data, TMEM101 is expressed in a wide range of tissues with low tissue specificity.[20] Relatively, it is expressed most highly in breast tissue, the seminal vesicles, the kidneys, and endometrial tissue.[20]

Expression in mouse embryo

Embryonic Development

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A cross section of a mouse embryo that has been stained for TMEM101 mRNA using in situ hybridization techniques shows noticeably lower levels of TMEM101 transcript in the liver than in other tissues.[21]

Differential Expression

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TMEM101 has been observed to be expressed at lower levels in ovarian endometriotic cells than in uterine endometrial cells within the same individuals.[22][23]

TMEM101 has also been observed to be expressed at higher levels in estrogen receptor positive ovarian cancer tumors than in estrogen receptor negative ovarian cancer tumors in mouse xenograft models.[24][25]

TMEM101 expression in ovarian endometriotic vs uterine endometrial cells
TMEM101 expression in ER positive vs ER negative ovarian tumors

Interacting Proteins

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The IntAct database indicates that the following proteins that have been found to interact with the TMEM101 protein through two-hybrid screening experiments.[26]

TMEM101 interacting proteins (from IntAct database)
Protein Description
BNIP3 BCL2/adenovirus E1B 19 kDA protein-interacting protein 3
C4orf3 Uncharacterized protein C4orf3
GIMAP1 GTPase IMAP family member 1
NDUFA3 NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3
NINJ2 Ninjurin-2
PDZK1IP1 PDZK1-interacting protein 1
PKMYT1 Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
STRIT1 Sarcoplasmic/endoplasmic reticulum calcium ATPase regulator DWORF
STX10 Syntaxin-10
SYNJ2BP Synaptojanin-2-binding protein
TMEM65 Transmembrane protein 65
TMEM243 Transmembrane protein 243
VAMP1 Vesicle-associated membrane protein 1
VAMP2 Vesicle-associated membrane protein 2
VAPB Vesicle-associated membrane protein-associated protein B/C

Homology and Evolution

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Orthologs and paralogs

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TMEM101 has orthologs in Mammalia, Sauropsida, Amphibia, Osteichthyes, Chondrichthyes, Mollusca, Annelida, Echinodermata, Cnidaria, and Placozoa, among others. A table of selected orthologs is listed below. There are no known paralogs of TMEM101.

Selected orthologs of the Homo sapiens TMEM101 protein
Genus and Species Common Name Taxonomic Group Estimated Date of Divergence (MYA) Accession Number Sequence Length (aa) Sequence Identity Sequence Similarity
Phascolarctos cinereus Koala Marsupialia 159 XP_020853077.1 257 89% 95%
Gallus gallus Chicken Aves 312 XP_003643860.1 257 80% 89%
Notechis scutatus Tiger snake Squamata 312 XP_026525463.1 257 79% 91%
Xenopus Tropicalis Tropical clawed frog Anura 351.8 NP_988884.1 255 76% 88%
Danio rerio Zebrafish Actinopterygii 435 NP_001314814.1 255 72% 86%
Acanthaster planci Crown-of-thorns starfish Echinodermata 684 XP_022105916.1 252 34% 51%
Crassotrea gigas Pacific oyster Mollusca 797 XP_011422883.2 251 30% 51%
Pocillopora damicornis Lace coral Cnidaria 824 XP_027044925.1 264 32% 52%
Trichoplax adhaerens Trichoplax Placozoa 948 XP_002108737.1 260 28% 51%
Relative protein evolution rates of TMEM101, Cytochrome c, and Fibrinogen alpha

Evolutionary History

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The most distantly related species to humans that possesses an ortholog of TMEM101 is Trichoplax adhaerens. Given that Ctenophorans do not possess orthologs of TMEM101, it appears that TMEM101 originated in the basal ParaHoxozoa clade after its divergence from Ctenophora approximately 948 million years ago. Based on a molecular clock analysis, the protein sequence of TMEM101 has on average evolved faster than Cytochrome c but slower than Fibrinogen alpha.

Function

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Activation of NF-κB Signaling Pathway

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TMEM101 cDNA transcripts have been demonstrated to activate the transcription of NF-κB controlled genes in human embryonic kidney cells.[6]

Clinical Significance

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TMEM101 has been noted as a biomarker of breast cancer. High expression of TMEM101 is associated with the Luminal molecular subtype of breast cancer.[7] Additionally, high levels of TMEM101 are associated with an increased risk score for the diagnosis of early stage triple-negative breast cancer.[27]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000091947 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020921 – 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. ^ a b c d e f g "TMEM101 transmembrane protein 101 [ Homo sapiens (human) ]". NCBI. Retrieved 22 October 2020.
  6. ^ a b Matsuda, A; Suzuki, Y; Honda, G; Muramatsu, S; Matsuzaki, O; Nagano, Y; Doi, T; Shimotohno, K; Harada, T; Nishida, E; Hayashi, H; Sugano, S (22 May 2003). "Large-scale identification and characterization of human genes that activate NF-κB and MAPK signaling pathways". Oncogene. 22 (21): 3307–3318. doi:10.1038/sj.onc.1206406. PMID 12761501.
  7. ^ a b Krijgsman, O; Roepman, P; Zwart, W; Carroll, J; Tian, S; Snoo, F; Bender, R; Bernards, R; Glas, A (4 August 2011). "A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response". Breast Cancer Research and Treatment. 133 (1): 37–47. doi:10.1007/s10549-011-1683-z. PMID 21814749. S2CID 8360858. Retrieved 22 October 2020.
  8. ^ "TMEM101 Gene (Protein Coding)". GeneCards. Retrieved 22 October 2020.
  9. ^ a b "Compute pI/Mw tool". Expasy. Retrieved 16 December 2020.
  10. ^ a b "SAPS". EMBL-EBI. Retrieved 16 December 2020.
  11. ^ "transmembrane protein 101 isoform a [Homo sapiens]". NCBI Protein. Retrieved 16 December 2020.
  12. ^ "Ali2D". MPI Bioinformatics Toolkit. Retrieved 16 December 2020.
  13. ^ a b "I-TASSER". Zhang Lab. Retrieved 16 December 2020.
  14. ^ "Phyre2". Structural Bioinformatics Group. Retrieved 16 December 2020.
  15. ^ "GPS-PAIL". The Cuckoo Workgroup. Retrieved 17 December 2020.
  16. ^ "GPS". The Cuckoo Workgroup. Retrieved 17 December 2020.
  17. ^ "Cell atlas - TMEM101". The Human Protein Atlas. Retrieved 16 December 2020.
  18. ^ "Gene2Promoter". Genomatix Software Suite. Retrieved 17 December 2020.
  19. ^ "MatInspector". Genomatix Software Suite. Retrieved 17 December 2020.
  20. ^ a b "Tissue Expression of TMEM101". The Human Protein Atlas. Retrieved 17 December 2020.
  21. ^ "EB1154 - TMEM101". Genepaint. Retrieved 17 December 2020.
  22. ^ "TMEM101 - Ovarian endometriosis". NCBI GEO. Retrieved 17 December 2020.
  23. ^ Hever, Aniko; Roth, Richard B.; Hevezi, Peter; Marin, Maria E.; Acosta, Jose A.; Acosta, Hector; Rojas, Jose; Herrera, Rosa; Grigoriadis, Dimitri; White, Evan; Conlon, Paul J.; Maki, Richard A.; Zlotnik, Albert (24 July 2007). "Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator". PNAS. 104 (30): 12451–12456. Bibcode:2007PNAS..10412451H. doi:10.1073/pnas.0703451104. PMC 1941489. PMID 17640886.
  24. ^ "Ovarian cancer intraperitoneal xenograft model". NCBI GEO. Retrieved 17 December 2020.
  25. ^ Spillman, Monique A.; Manning, Nicole G.; Dye, Wendy W.; Sartorius, Carol A.; Post, Miriam D.; Harrell, Joshua Chuck; Jacobsen, Britta M.; Horwitz, Kathryn B. (November 2010). "Tissue-Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis". Cancer Research. 70 (21): 8927–8936. doi:10.1158/0008-5472.CAN-10-1238. PMC 3804411. PMID 20959477. Retrieved 17 December 2020.
  26. ^ "IntAct Molecular Interaction Database". EMBL-EBI. Retrieved 17 December 2020.
  27. ^ Ren, Y., Jiang, Y., Zuo, W., Xu, X., Jin, X., Ma, D., & Shao, Z. (2019). Abstract P2-08-33: A novel seven-gene signature predicts prognosis in early-stage triple-negative breast cancer. Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4–8, 2018; San Antonio, Texas, 79(4). https://doi.org/10.1158/1538-7445.sabcs18-p2-08-33
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