DMAC1 explained

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 and Distal membrane-arm assembly complex protein 1.[2]

Gene features

TMEM261 is located at 9p24.1, its length is 91,891 base pairs (bp) on the reverse strand. Its neighbouring gene is PTPRD located at 9p23-p24.3 also on the reverse strand and encodes protein tyrosine phosphatase receptor type delta.[1] [3] 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]

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

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] 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[3] [26] and two binding sites for GATA1 which is a globin transcription factor 1 involved in erythroblast development regulation.[27] [28] [29]

Expression

TMEM261 shows ubiquitous expression in humans and is detected in almost all tissue types.[30] [31] It shows tissue-enriched gene (TEG) expression when compared to housekeeping gene (HKG) expression. 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.[30] Staining intensity of cancer cells showed intermediate to high expression in breast, colorectal, ovarian, skin, urothelial, head and neck cells.[30]

Function

Currently the function for TMEM261 is unknown.[32] However, gene amplification and rearrangements of its locus have been associated with various cancers including colorectal cancer,[33] breast cancer[34] and lymphomas.[35] [36]

Evolution

Orthologues

The orthologues and homologues of TMEM261 are limited to vertebrates, its oldest homologue dates to that of the cartilaginous fishes[37] which diverged from Homo sapiens 462.5 million years ago.[38] 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
Homo sapiens NP_219500.1 0 112 100 Mammalia
Gorilla gorilla XP_004047847.1 8.8 112 99 Mammalia
Papio anubis XP_003911767.1 29 112 84 Mammalia
Galeopterus variegatus XP_008587957.1 81.5 112 68 Mammalia
Jaculus Jaculus XP_004653029.1 92.3 109 56 Mammalia
Heterocephalus glaber XP_004898193.1 92.3 114 45 Mammalia
Ceratotherium simum simum XP_004436891.1 94.2 112 66 Mammalia
Dasypus novemcinctus XP_004459147.1 104.4 112 59 Mammalia
Chelonia mydas XP_007056940.1 296 85 49 Reptilia
Taeniopygia Guttata XP_002187613.2 296 72 47 Aves
Xenopus tropicalis XP_002943025.1 371.2 85 45 Amphibia
Haplochromis burtoni Haplochromis burtoni XP_005928614.1 400.1 91 51 Actinopterygii
Callorhinchus milii XP_007884223.1 426.5 86 43 Chondrichthyes

Paralogues

TMEM261 has no known paralogs.[37]

External links

Further reading

Notes and References

  1. Web site: Entrez Protein: TMEM261.
  2. Web site: DMAC1 - Distal membrane-arm assembly complex protein 1 - Homo sapiens (Human) - DMAC1 gene & protein. www.uniprot.org. en. 2018-07-30.
  3. Web site: GeneCards: PTPRD.
  4. Thierry-Mieg. D. Thierry-Mieg, J.. AceView: a comprehensive cDNA-supported gene and transcripts annotation. Genome Biology. 2006. 7. Suppl 1. S12.1–14. 10.1186/gb-2006-7-s1-s12. 16925834. 1810549. free.
  5. Web site: AceView:Homo sapiens gene C9orf123.
  6. Web site: Ensemble:Transcript TMEM261-003.
  7. Web site: PI:Isoelectric point determination.
  8. Web site: NCBI Conserved Domains: DUF4536.
  9. Web site: EMBL-EBI Interpro: Transmembrane protein 261 (Q96GE9).
  10. Web site: Phobius: A combined transmembrane topology and signal peptide predictor.
  11. Web site: Q96GE9 - TM261_HUMAN. UniProt. UniProt Consortium.
  12. Web site: Vega: Transcript: C9orf123-003.
  13. Web site: PHYRE: Protein Homology/analogY Recognition Engine. PHYRE.
  14. Kelley. LA. Sternberg. MJE. Protein structure prediction on the Web: a case study using the Phyre server. Nature Protocols. 2009. 4. 3. 363–371. 10.1038/nprot.2009.2. 19247286. 10044/1/18157. 12497300. free.
  15. Web site: ClustalW.
  16. Thompson. Julie D. Higgins. Desmond G. Gibson. Toby J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.. Nucleic Acids Res. 1994. 22. 22. 4673–4680. 308517. 10.1093/nar/22.22.4673. 7984417.
  17. Web site: Gallo. Vincenzo. Myristoylation : Proteins Post-translational Modifications. flipper.diff.org. University of Turin.
  18. Web site: Nextprot:TMEM261 » Transmembrane protein 261.
  19. Dash A et al.. Changes in differential gene expression because of warm ischemia time of radical prostatectomy specimens.. Am J Pathol. 2002. 161. 5. 1743–1748. 10.1016/S0002-9440(10)64451-3. 12414521. 1850797.
  20. Rovillain E et al.. An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence.. BMC Genomics. 2011. 12. 355. 355. 10.1186/1471-2164-12-355. 21740549. 3161017 . free .
  21. Web site: c9orf123 protein (Homo Sapiens)- STRING Network View. STRING - Known and Predicted Protein-Protein Interactions.
  22. Oláh J et al.. Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein.. J Biol Chem. 2011. 286. 39. 34088–34100. 10.1074/jbc.M111.243907. 21832049. 3190826. free .
  23. Huttlin EL et al.. High-Throughput Proteomic Mapping of Human Interaction Networks via Affinity-Purification Mass Spectrometry (Pre-Publication). Pre-Publication. 2014.
  24. Lehner. B. Sanderson. C M. A protein interaction framework for human mRNA degradation.. Genome Res. . 2004. 14. 7. 1315–1323. 10.1101/gr.2122004. 15231747. 442147.
  25. Web site: 9ORF123 chromosome 9 open reading frame 123. BioGRID: Database of Protein and Genetic Interactions. TyersLab.
  26. Web site: GeneCards:MEF2C Gene .
  27. Welch JJ et al.. Global regulation of erythroid gene expression by transcription factor GATA-1.. Blood. 2004. 104. 10. 3136–3147. 15297311 . 10.1182/blood-2004-04-1603. free.
  28. Merryweather-Clarke AT et al.. Global gene expression analysis of human erythroid progenitors. Blood. 2011. 117. 13. e96-108. 10.1182/blood-2010-07-290825. 21270440. free.
  29. Web site: Genomatics- NGS Data Analysis and Personalised Medicine. Genomatix. Genomatix Software GmbH. 2015-05-07. 2001-02-24. https://web.archive.org/web/20010224072831/http://www.genomatix.de/. dead.
  30. Web site: The Human Protein Atlas:TMEM261.
  31. Web site: EST profile: TMEM261. UniGene. National Library of Medicine.
  32. Wu J et al.. Identification and functional analysis of 9p24 amplified genes in human breast cancer. Oncogene. 2012. 31. 3. 333–341. 10.1038/onc.2011.227. 21666724. 3886828.
  33. Gaspar. C. Cross-Species Comparison of Human and Mouse Intestinal Polyps Reveals Conserved Mechanisms in Adenomatous Polyposis Coli (APC)-Driven Tumorigenesis. Am J Pathol. 2008. 172. 5. 1363–1380. 10.2353/ajpath.2008.070851. 18403596 . 2329845.
  34. Wu. J. Identification and functional analysis of 9p24 amplified genes in human breast cancer. Oncogene. 2012. 31. 3. 333–341. 10.1038/onc.2011.227. 21666724. 3886828.
  35. Twa DD et al.. Genomic Rearrangements Involving Programmed Death Ligands Are Recurrent in Primary Mediastinal Large B-Cell Lymphoma. Blood. 2014. 123. 13. 2062–2065. 10.1182/blood-2013-10-535443. 24497532. free.
  36. Green MR et al.. 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. 2010. 116. 17. 3268–3277. 10.1182/blood-2010-05-282780. 20628145. 2995356.
  37. Web site: NCBI BLAST:Basic Local Alignment Search Tool.
  38. Hedges. S. Blaire. Dudley. Joel. Kumar. Sudhir. TimeTree: a public knowledge-base of divergence times among organisms. 22 September 2006. 22. 23. 2971–2972. 10.1093/bioinformatics/btl505. 17021158. Bioinformatics. 7 May 2015. https://web.archive.org/web/20150505113900/http://kumarlab.net/pdf_new/HedgesKumar06.pdf. 5 May 2015. dead. free.

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