DMAC1

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

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n/a

RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
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Transmembrane protein 261 is a protein that in humans is encoded by the TMEM261 gene located on chromosome 9.[1] TMEM261 is also known as C9ORF123 and DMAC1, Chromosome 9 Open Reading Frame 123 and Transmembrane Protein C9orf123[2] and Distal membrane-arm assembly complex protein 1[3].

Gene Features


TMEM261 is located at 9p24.1, its length is 91,891 base pairs (bp) on the reverse strand.[2] Its neighbouring gene is PTPRD located at 9p23-p24.3 also on the reverse strand and encodes protein tyrosine phosphatase receptor type delta.[1][2] TMEM261 has 2 exons and 1 intron, and 6 primary transcript variants; the largest mRNA transcript variant consisting of 742bp with a protein 129 amino acids (aa) in length and 13,500 Daltons (Da) in size, and the smallest coding transcript variant being 381bp with a protein 69aa long and 6,100 Da in size.[4][5]

File:TMEM261 features.jpg
Annotated features of TMEM261 protein including topology and important sites for phosphorylation and Myristoylation as well DUF4536 and transmembrane helical domains.

Protein Features

TMEM261 is a protein consisting out of 112 amino acids, with a molecular weight of 11.8 kDa.[6] The isoelectric point is predicted to be 10.2,[7] whilst its posttranslational modification value is 9.9.[5]

Structure

File:TMEM261interactions.jpg
Some proteins found to interact with TMEM261

TMEM261 contains a domain of unknown function, DUF4536 (pfam15055), predicted as a helical membrane spanning domain about 45aa (Cys 47- Ser 92) in length with no known domain relationships.[8][9] Two further transmembrane helical domains are predicted of lengths 18aa (Val 52-Ala 69) and 23aa (Pro 81-Ala 102]).[10][11] There is also a low complexity region spanning 25aa (Thr 14-Ala 39).[12] The tertiary structure for TMEM261 has not yet been determined. However, its protein secondary structure is mostly composed of coiled-coil regions with beta strands and alpha helices found within the transmembrane and domain of unknown function regions. The N-terminal region of TMEM261 is composed of a disordered region[13][14] which contains the low complexity region[12] that is not highly conserved amongst orthologues.[15][16]

Modifications

A N-myristoylation domain is shown to be present in most TMEM261 protein variants.[5] Post-translational modifications include myristoylation of the N-terminal Glycine residue (Gly2)[5][17] of the TMEM261 protein as well as phosphorylation of Threonine 31.[18]

Interactions

Proteins shown to interact with TMEM261 include NAAA (protein-protein interaction), QTRT1 (RNA-protein interaction),ZC4H2(DNA-protein interaction)[19] and ZNF454(DNA-protein interaction).[20][21] It has also shown to interact with APP(protein-protein interaction),[22] ARHGEF38(protein-protein interaction)[23] and HNRNPD(RNA-protein interaction).[24][25]

File:Tissueexpression.jpg
Tissue expression of TMEM261 showing tissue enriched gene (TEG) expression [26]

Additional transcription factor binding sites (DNA-protein interaction) predicted include one binding site for MEF2C a monocyte-specific enhancement factor that is involved in muscle-cell regulation particularly in the cardiovascular system [2][27] and two binding sites for GATA1 which is a globin transcription factor 1 involved in erythroblast development regulation.[28][29][30]

Expression

TMEM261 shows ubiquitous expression in humans and is detected in almost all tissue types.[31][32] It shows tissue-enriched gene (TEG) expression when compared to housekeeping gene (HKG) expression.[26] Its highest expression is seen in the heart (overall relative expression 94%) particularly in heart fibroblast cells, thymus (overall relative expression 90%), and thyroid (overall relative expression 93%) particularly in thyroid glandular cells.[26][31] Staining intensity of cancer cells showed intermediate to high expression in breast, colorectal, ovarian, skin, urothelial, head and neck cells.[31]

Function

Currently the function for TMEM261 is unknown.[33] However, gene amplification and rearrangements of its locus have been associated with various cancers including colorectal cancer,[34] breast cancer[35] and lymphomas.[36][37]

Evolution

Orthologues

The orthologues and homologues of TMEM261 are limited to vertebrates, its oldest homologue dates to that of the cartilaginous fishes[38] which diverged from Homo sapiens 462.5 million years ago.[39] The protein primary structure of TMEM261 shows higher overall conservation in mammals, however high conservation of the domain of unknown function (DUF4536) to the C-terminus region is seen in all orthologues, including distant homologues. The protein structure of TMEM261 shows conservation across most orthologues.[15][16]

Organism Scientific Name Accession Number Date of Divergence from Humans (million years) Amino acids (aa) Identity (%) Class
Humans Homo sapiens NP_219500.1 0 112 100 Mammalia
Gorilla Gorilla gorilla XP_004047847.1 8.8 112 99 Mammalia
Olive baboon Papio anubis XP_003911767.1 29 112 84 Mammalia
Sunda flying lemur Galeopterus variegatus XP_008587957.1 81.5 112 68 Mammalia
Lesser Egyptian jerboa Jaculus Jaculus XP_004653029.1 92.3 109 56 Mammalia
Naked mole rat Heterocephalus glaber XP_004898193.1 92.3 114 45 Mammalia
White rhinoceros Ceratotherium simum simum XP_004436891.1 94.2 112 66 Mammalia
Nine-banded armadillo Dasypus novemcinctus XP_004459147.1 104.4 112 59 Mammalia
Green sea turtle Chelonia mydas XP_007056940.1 296 85 49 Reptilia
Zebra finch Taeniopygia Guttata XP_002187613.2 296 72 47 Aves
Western clawed frog Xenopus tropicalis XP_002943025.1 371.2 85 45 Amphibia
Haplochromis burtoni Haplochromis burtoni XP_005928614.1 400.1 91 51 Actinopterygii
Australian ghost shark Callorhinchus milii XP_007884223.1 426.5 86 43 Chondrichthyes

Paralogues

TMEM261 has no known paralogs.[38]

References

  1. 1.0 1.1 "Entrez Protein: TMEM261".
  2. 2.0 2.1 2.2 2.3 "GeneCards: PTPRD".
  3. "DMAC1 - Distal membrane-arm assembly complex protein 1 - Homo sapiens (Human) - DMAC1 gene & protein". www.uniprot.org. Retrieved 2018-07-30.
  4. Thierry-Mieg, D; Thierry-Mieg, J. (2006). "AceView: a comprehensive cDNA-supported gene and transcripts annotation". Genome Biology. 7 (Suppl 1): S12. doi:10.1186/gb-2006-7-s1-s12. PMC 1810549. PMID 16925834.
  5. 5.0 5.1 5.2 5.3 "AceView:Homo sapiens gene C9orf123".
  6. "Ensemble:Transcript TMEM261-003".
  7. "PI:Isoelectric point determination".
  8. "NCBI Conserved Domains: DUF4536".
  9. "EMBL-EBI Interpro: Transmembrane protein 261 (Q96GE9)".
  10. "Phobius: A combined transmembrane topology and signal peptide predictor".
  11. "Q96GE9 - TM261_HUMAN". UniProt. UniProt Consortium.
  12. 12.0 12.1 "Vega: Transcript: C9orf123-003".
  13. "PHYRE: Protein Homology/analogY Recognition Engine". PHYRE.
  14. Kelley, LA; Sternberg, MJE (2009). "Protein structure prediction on the Web: a case study using the Phyre server". MJE. 4: 363–371. doi:10.1038/nprot.2009.2. PMID 19247286.
  15. 15.0 15.1 "ClustalW".
  16. 16.0 16.1 Thompson, Julie D; Higgins, Desmond G; Gibson, Toby J (1994). "CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice". Nucleic Acids Res. 22 (22): 4673–4680. doi:10.1093/nar/22.22.4673. PMC 308517. PMID 7984417.
  17. Gallo, Vincenzo. "Myristoylation : Proteins Post-translational Modifications". flipper.diff.org. University of Turin.
  18. "Nextprot:TMEM261 » Transmembrane protein 261".
  19. Dash A, et al. (2002). "Changes in differential gene expression because of warm ischemia time of radical prostatectomy specimens". Am J Pathol. 161 (5): 1743–1748. doi:10.1016/S0002-9440(10)64451-3. PMC 1850797. PMID 12414521.
  20. Rovillain E, et al. (2011). "An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence". BMC Genomics. 12 (355). doi:10.1186/1471-2164-12-355. PMC 3161017. PMID 21740549.
  21. "c9orf123 protein (Homo Sapiens)- STRING Network View". STRING - Known and Predicted Protein-Protein Interactions.
  22. Oláh J, et al. (2011). "Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein". J Biol Chem. 286 (39): 34088–34100. doi:10.1074/jbc.M111.243907. PMC 3190826. PMID 21832049.
  23. Huttlin EL, et al. (2014). "High-Throughput Proteomic Mapping of Human Interaction Networks via Affinity-Purification Mass Spectrometry (Pre-Publication)". Pre-Publication.
  24. Lehner, B; Sanderson, C M (2004). "A protein interaction framework for human mRNA degradation". Genome Res. 14 (7): 1315–1323. doi:10.1101/gr.2122004. PMC 442147. PMID 15231747.
  25. "9ORF123 chromosome 9 open reading frame 123". BioGRID: Database of Protein and Genetic Interactions. TyersLab.
  26. 26.0 26.1 26.2 She X, Rohl CA, Castle JC, Kulkarni AV, Johnson JM, Chen R (2009). "Definition, conservation and epigenetics of housekeeping and tissue-enriched genes". BMC Genomics. 10: 269. doi:10.1186/1471-2164-10-269. PMC 2706266. PMID 19534766.
  27. "GeneCards:MEF2C Gene".
  28. Welch JJ, et al. (2004). "Global regulation of erythroid gene expression by transcription factor GATA-1". Blood. 104 (10): 3136–3147. doi:10.1182/blood-2004-04-1603. PMID 15297311.
  29. Merryweather-Clarke AT, et al. (2011). "Global gene expression analysis of human erythroid progenitors". Blood. 117 (13): e96–108. doi:10.1182/blood-2010-07-290825. PMID 21270440.
  30. "Genomatics- NGS Data Analysis and Personalised Medicine". Genomatix. Genomatix Software GmbH.
  31. 31.0 31.1 31.2 "The Human Protein Atlas:TMEM261".
  32. "EST profile: TMEM261". UniGene. National Library of Medicine.
  33. Wu J, et al. (2012). "Identification and functional analysis of 9p24 amplified genes in human breast cancer". Oncogene. 31 (3): 333–341. doi:10.1038/onc.2011.227. PMC 3886828. PMID 21666724.
  34. Gaspar, C (2008). "Cross-Species Comparison of Human and Mouse Intestinal Polyps Reveals Conserved Mechanisms in Adenomatous Polyposis Coli (APC)-Driven Tumorigenesis". Am J Pathol. 172 (5): 1363–1380. doi:10.2353/ajpath.2008.070851. PMC 2329845. PMID 18403596.
  35. Wu, J (2012). "Identification and functional analysis of 9p24 amplified genes in human breast cancer". Oncogene. 31 (3): 333–341. doi:10.1038/onc.2011.227. PMC 3886828. PMID 21666724.
  36. Twa DD, et al. (2014). "Genomic Rearrangements Involving Programmed Death Ligands Are Recurrent in Primary Mediastinal Large B-Cell Lymphoma". Blood. 123 (13): 2062–2065. doi:10.1182/blood-2013-10-535443. PMID 24497532.
  37. Green MR, et al. (2010). "Integrative Analysis Reveals Selective 9p24.1 Amplification, Increased PD-1 Ligand Expression, and Further Induction via JAK2 in Nodular Sclerosing Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma". Blood. 116 (17): 3268–3277. doi:10.1182/blood-2010-05-282780. PMC 2995356. PMID 20628145.
  38. 38.0 38.1 "NCBI BLAST:Basic Local Alignment Search Tool".
  39. Hedges, S. Blaire; Dudley, Joel; Kumar, Sudhir (22 September 2006). "TimeTree: a public knowledge-base of divergence times among organisms" (PDF). Bioinformatics. 22 (23): 2971–2972. doi:10.1093/bioinformatics/btl505. PMID 17021158.

External links

Further reading

  • Nicholas K. Tonks (2006). "Protein tyrosine phosphatases: from genes, to function, to disease". Cancer Cell. 7: 833–846. doi:10.1038/nrm2039.
  • Merryweather-Clarke AT, et al. (2011). "Global gene expression analysis of human erythroid progenitors". Blood. 117 (13): e96–108. doi:10.1182/blood-2010-07-290825. PMID 21270440.
  • Welch JJ, Watts JA, Vakoc CR, et al. (2004). "Global regulation of erythroid gene expression by transcription factor GATA-1". Blood. 104 (10): 3136–3147. doi:10.1182/blood-2004-04-1603. PMID 15297311.
  • Nickeleit I, et al. (2008). "Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition". Cancer Cell. 14 (1): 23–35. doi:10.1016/j.ccr.2008.05.016. PMID 18598941.