Biology:TMEM171

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Transmembrane protein 171 (TMEM171) is a protein that in humans is encoded by the TMEM171 gene.[1]

Gene

General properties

TMEM171 is also known as PRP2 or proline-rich protein 2. It has 11,526 base pairs and 4 exons and is located on the long arm of chromosome 5, at 5q13.2, in humans.[2] It spans from 73,120,292 to 73,131,817 on the plus strand. It is flanked by FCHO2 and TNPO1 upstream and TMEM174 downstream.[2]

Promoter

The predicted promoter region (GXP_7598) is 2034 base pairs long and extends past the first exon of TMEM171.[3] Transcription factors predicted to bind to the promoter region include p63 tumor protein, CCCTC binding factors, TATA binding factors, and thyroid hormone receptors.[4]

Expression

TMEM171 is moderately and differentially expressed, indicating that it is neither a housekeeping gene nor a tissue-enriched gene.[5][6] Its expression is highest in the thyroid, mammary gland, stomach, duodenum, and kidney. It is also expressed at moderate levels in tissues including the spleen, ileum, colon, salivary gland, and expressed at lower levels in a variety of other tissues.[7] Conditional expression patterns of TMEM171 include decreased expression in papillary thyroid carcinoma, colon cancer, and gastric cancer, as well as increased expression in p63-depleted tissue and induced alveolar macrophages.[8][9][10][11][12]

Expression profile of TMEM171 in a selection of normal tissues

mRNA

TMEM171 has isoforms 1, 2, and X1, with 4 exons each.[1] The 3 transcripts undergo alternate in-frame splicing and are translated into proteins with 324, 323, and 305 amino acids, respectively.[13][14][15]

RNA-binding proteins

The 5' untranslated region has predicted sites for binding by SFRS1 and SFRS9 splicing factors and FUS, which couples transcription and splicing. The 3' untranslated region has predicted sites for binding by ELAVL1 and ZFP36, which both bind AU rich elements and may compete to stabilize or destabilize the mRNA.[16]

Protein

General properties

The longest protein isoform of TMEM171 is 324 amino acids in length and has an observed molecular weight of approximately 44 kDa.[13][17] TMEM171 is an acidic protein overall, with a predicted isoelectric point of approximately 5.[18]

Composition

TMEM171 has fewer lysine residues than expected for a human protein.[19] Despite the fact that its alias is proline-rich protein 2, TMEM171 in humans does not have more proline residues than expected; however it does have a multiplet of 6 proline residues. More distant orthologs, including Xenopus tropicalis, do have significantly more proline residues than expected. TMEM171 has 3 hydrophobic segments, which correspond with transmembrane regions.[19]

Domains and motifs

Schematic illustration of TMEM171, with domains and post-translational modifications.

TMEM171 has a conserved domain, pfam15471 (aa4:318), whose structure and function are not yet characterized.[1] Within the domain, there are 4 transmembrane domains, 2 non-cytosolic domains, and 3 cytosolic domains.

Structure

The structure of TMEM171 consists of approximately 25% beta strands and 15% alpha helices, with coils and disordered regions making up the rest of the structure.[20] The tertiary structure includes 2 predicted disulfide bridges, which occur between highly conserved cysteine residues in the non-cytosolic domains.[21]

Predicted structure of TMEM171, with 4 transmembrane (purple), 3 cytosolic (blue), and 2 non-cytosolic (red) domains. Predicted by I-TASSER and viewed with EzMol.[22][23]

Post-translational modifications

TMEM171 undergoes methionine cleavage and N-terminal acetylation, which is one of the most common modifications of eukaryotic proteins.[24] N-linked glycosylation is predicted at a highly conserved NETD sequence within a non-cytosolic domain.[25] S-palmitoylation, which enhances surface hydrophobicity and membrane affinity, is predicted at 2 cytosolic cysteine residues in TMEM171.[26] TMEM171 is phosphorylated by unspecified kinases at several sites.[27] It also undergoes O-ß-GlcNAc modification at 4 sites, 3 of which are Yin-Yang sites due to O-ß-GlcNAc modification and phosphorylation competing for control of protein activation or deactivation.[28]

Conceptual translation of TMEM171, with predicted post-translational modifications.

Localization

TMEM171's predicted location is in the plasma membrane, with both the N- and C-termini located inside the cell.[29][30]

Interacting proteins

The proteins that are most likely to interact with TMEM171, based on affinity chromatography and two hybrid arrays, are MIER1, EMSY, CHPT1, HDLBP, NEDD4, WWOX, and TTHY3.[31] There is strong evidence for a direct interaction between TMEM171 an MIER1, which is a transcriptional repressor that is associated with central hypothyroidism.[32]

Clinical significance

TMEM171 is down-regulated in papillary thyroid carcinoma and two SNPs, with the non-synonymous mutations R86G and N139K, are identified risk SNPs for papillary thyroid carcinoma.[33][34][35] TMEM171 is also down-regulated in gastric cancer and colon cancer.[9][10] More specifically, it is down-regulated in right-sided colon cancer relative to left-sided colon cancer, which typically has a better prognosis.[36] In renal cancer, high expression of TMEM171 is a favorable prognostic marker.[37] In triple-negative breast cancer cells, immuno-activation by tumor necrosis factor alpha (TNFα) was found to up-regulate TMEM171.[38]

Evolution

TMEM171 has signatures of balancing selection, which include a significant excess of polymorphisms and intermediate-frequency alleles.[39]

Homology

TMEM171 has no paralogs or paralogous domains. TMEM171 has 208 identified orthologs.[1] All orthologs are vertebrates, including mammals, amphibians, reptiles, birds, lobe-finned fish, and cartilaginous fish. The following table provides a sample of the ortholog space of TMEM171.

Genus and Species NCBI Accession Number Date of Divergence (MYA)[40] Sequence Length Sequence Identity[41]
Homo sapiens (Human) NP_775761.4 0 324 100%
Pan troglodytes (Chimpanzee) XP_009447304.1 6 324 99%
Saimiri boliveiensis (Black-capped squirrel monkey)   XP_010334830.1  42.6 324 91%
Mus musculus (Mouse) XP_006517772.1 88 323 75%
Myotis lucifugus (Little brown bat) XP_006081400.1 94 325 82%
Vulpes vulpes (Fox) XP_025838976.1 94 321 73%
Chrysochloris asiatica  (Cape golden mole) XP_006875335.1  102 326 73%
Sarcophilus harrisii (Tasmanian devil) XP_003759514.1 160 332 67%
Empidonax traillii (Willow flycatcher) XP_027739189.1 320 333 52%
Anas platyrhynchos (Mallard) XP_027302666.1  320 330 47%
Xenopus tropicalis (Western clawed frog) XP_012815192.1 353 332 54%
Rhincodon typus (Whale shark) XP_020374629.1   465 311 36%
Callorhinchus milii (Australian ghost shark; Elephant fish) XP_007898003.1 465 293 31%

References

  1. ↑ 1.0 1.1 1.2 1.3 National Center for Biotechnology Information. "Transmembrane Protein 171". https://www.ncbi.nlm.nih.gov/gene/134285. 
  2. ↑ 2.0 2.1 Weizmann Institute of Science. "TMEM171 Gene". https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM171. 
  3. ↑ Intrexon Bioinformatics Germany GmbH. "El Dorado: Genome Annotation and Browser". https://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=80a5a9ac678dcfd368e56aba997bbf09. 
  4. ↑ Intrexon Bioinformatics Germany GmbH. "MatInspector". https://www.genomatix.de/cgi-bin/matinspector_prof/mat_fam.pl?s=80a5a9ac678dcfd368e56aba997bbf09. 
  5. ↑ "Definition, conservation and epigenetics of housekeeping and tissue-enriched genes". BMC Genomics 10 (1): 269. June 2009. doi:10.1186/1471-2164-10-269. PMID 19534766. 
  6. ↑ "A comprehensive functional analysis of tissue specificity of human gene expression". BMC Biology 6 (1): 49. November 2008. doi:10.1186/1741-7007-6-49. PMID 19014478. 
  7. ↑ National Center for Biotechnology Information (NCBI). "GDS3834 Profile". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3834:16164. 
  8. ↑ National Center for Biotechnology Information (NCBI). "GDS1665 Expression Profile". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS1665:1553559_at. 
  9. ↑ 9.0 9.1 "Identification of Key Genes and Circular RNAs in Human Gastric Cancer". Medical Science Monitor 25: 2488–2504. April 2019. doi:10.12659/MSM.915382. PMID 30948703. PMC 6463957. https://www.medscimonit.com/abstract/index/idArt/915382. 
  10. ↑ 10.0 10.1 Yang, Wanli; Ma, Jiaojiao; Zhou, Wei; Li, Zichao; Zhou, Xin; Cao, Bo; Zhang, Yujie; Liu, Jinqiang et al. (2018-12-27). "Identification of hub genes and outcome in colon cancer based on bioinformatics analysis" (in English). Cancer Management and Research 11: 323–338. doi:10.2147/cmar.s173240. PMID 30643458. 
  11. ↑ National Center for Biotechnology Information (NCBI). "GDS2534 Expression Profile". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS2534:240770_at. 
  12. ↑ National Center for Biotechnology Information (NCBI). "GDS4419 Expression Profile". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS4419:1553559_at. 
  13. ↑ 13.0 13.1 National Center for Biotechnology Information. "Transmembrane protein 171 isoform 1". https://www.ncbi.nlm.nih.gov/protein/NP_775761.4. 
  14. ↑ National Center for Biotechnology Information. "Transmembrane Protein 171 isoform 2". https://www.ncbi.nlm.nih.gov/protein/NP_001154814.1. 
  15. ↑ National Center for Biotechnology Information. "Transmembrane protein 171 isoform X1". https://www.ncbi.nlm.nih.gov/protein/XP_011541458.1. 
  16. ↑ "RBPDB: The database of RNA-binding protein specificities". http://rbpdb.ccbr.utoronto.ca/. 
  17. ↑ "Anti-TMEM171 Antibody". https://www.sigmaaldrich.com/catalog/product/sigma/hpa042308?lang=en&region=US. 
  18. ↑ Swiss Institute of Bioinformatics. "Compute pI/Mw Tool". https://web.expasy.org/compute_pi/. 
  19. ↑ 19.0 19.1 European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI). "Statistical Analysis of Protein Sequences (SAPS)". https://www.ebi.ac.uk/Tools/seqstats/saps/. 
  20. ↑ "SOPMA Secondary Structure Prediction Method". https://npsa-prabi.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsa_sopma.html. 
  21. ↑ Machine Learning & Neural Networks Group. "Disulfind". http://disulfind.dsi.unifi.it/. 
  22. ↑ University of Michigan. "I-TASSER Protein Structure & Function Predictions". https://zhanglab.ccmb.med.umich.edu/I-TASSER/. 
  23. ↑ "EzMol: A Web Server Wizard for the Rapid Visualization and Image Production of Protein and Nucleic Acid Structures". Journal of Molecular Biology 430 (15): 2244–2248. July 2018. doi:10.1016/j.jmb.2018.01.013. PMID 29391170. 
  24. ↑ "N-Acetylation and initial methionine predictor". http://terminus.unige.ch/. 
  25. ↑ "NetNGlyc 1.0 Server". http://www.cbs.dtu.dk/services/NetNGlyc/. 
  26. ↑ The Cuckoo Workgroup. "CSS-Palm: Prediction of Palmitoylation Site". http://csspalm.biocuckoo.org/online.php. 
  27. ↑ Blom, Nikolaj. "Net Phos 3.1 Server". http://www.cbs.dtu.dk/services/NetPhos/. 
  28. ↑ Gupta, Ramneek. "YinOYang1.2". http://www.cbs.dtu.dk/services/YinOYang/. 
  29. ↑ Yachdav, D. and Rost, B.. "Predict Protein". https://www.predictprotein.org/. 
  30. ↑ "Phobius". http://phobius.sbc.su.se/. 
  31. ↑ "mentha: a resource for browsing integrated protein-interaction networks". Nature Methods 10 (8): 690–1. August 2013. doi:10.1038/nmeth.2561. PMID 23900247. https://zenodo.org/record/924817. 
  32. ↑ Weizmann Institute of Science. "MIER1Gene". https://www.genecards.org/cgi-bin/carddisp.pl?gene=MIER1#diseases. 
  33. ↑ "Network-based meta-analysis in the identification of biomarkers for papillary thyroid cancer". Gene 661: 160–168. June 2018. doi:10.1016/j.gene.2018.03.096. PMID 29625265. 
  34. ↑ "Genome-wide gene expression profiles of thyroid carcinoma: Identification of molecular targets for treatment of thyroid carcinoma". Oncology Reports 20 (1): 105–21. July 2008. doi:10.3892/or.20.1.105. PMID 18575725. http://www.spandidos-publications.com/or/20/1/105/download. 
  35. ↑ "Investigating the mechanisms of papillary thyroid carcinoma using transcriptome analysis". Molecular Medicine Reports 16 (5): 5954–5964. November 2017. doi:10.3892/mmr.2017.7346. PMID 28849102. 
  36. ↑ "Microarray‑based analysis of COL11A1 and TWIST1 as important differentially‑expressed pathogenic genes between left and right‑sided colon cancer". Molecular Medicine Reports 20 (5): 4202–4214. November 2019. doi:10.3892/mmr.2019.10667. PMID 31545476. 
  37. ↑ "Expression of TMEM171 in renal cancer - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000157111-TMEM171/pathology/renal+cancer. 
  38. ↑ "Whole Transcriptomic Analysis of Apigenin on TNFα Immuno-activated MDA-MB-231 Breast Cancer Cells". Cancer Genomics & Proteomics 16 (6): 421–431. 2019. doi:10.21873/cgp.20146. PMID 31659097. 
  39. ↑ "Targets of balancing selection in the human genome". Molecular Biology and Evolution 26 (12): 2755–64. December 2009. doi:10.1093/molbev/msp190. PMID 19713326. 
  40. ↑ Temple University Center of Biodiversity. "Pairwise Divergence Time". http://www.timetree.org/. 
  41. ↑ National Center for Biotechnology Information. "Standard Protein BLAST". https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE=Proteins&PROGRAM=blastp&PAGE_TYPE=BlastSearch&BLAST_SPEC=. 



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