Biology:DMAC1

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Distal membrane-arm assembly complex protein 1 is a protein that in humans is encoded by the DMAC1 gene (previously TMEM261).[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]

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

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]

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[33] 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
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.[37]

References

  1. ↑ 1.0 1.1 "Entrez Protein: TMEM261". https://www.ncbi.nlm.nih.gov/gene/90871. 
  2. ↑ 2.0 2.1 2.2 2.3 "GeneCards: PTPRD". https://www.genecards.org/cgi-bin/carddisp.pl?gene=PTPRD&search=ec5eebdfa3e88e99844e476b922bd273. 
  3. ↑ "DMAC1 - Distal membrane-arm assembly complex protein 1 - Homo sapiens (Human) - DMAC1 gene & protein". https://www.uniprot.org/uniprot/Q96GE9. 
  4. ↑ "AceView: a comprehensive cDNA-supported gene and transcripts annotation". Genome Biology 7 Suppl 1 (Suppl 1): S12.1–14. 2006. doi:10.1186/gb-2006-7-s1-s12. PMID 16925834. 
  5. ↑ 5.0 5.1 5.2 5.3 "AceView:Homo sapiens gene C9orf123". https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=c9orf123&submit=Go. 
  6. ↑ "Ensemble:Transcript TMEM261-003". http://www.ensembl.org/Homo_sapiens/Transcript/Summary?db=core;g=ENSG00000137038;r=9:7796490-7888380;t=ENST00000358227. 
  7. ↑ "PI:Isoelectric point determination". http://workbench.sdsc.edu/. 
  8. ↑ NIH/NLM/NCBI/IEB/CDD group. "NCBI Conserved Domains: DUF4536". https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=259192. 
  9. ↑ European Bioinformatics Institute. "EMBL-EBI Interpro: Transmembrane protein 261 (Q96GE9)". http://www.ebi.ac.uk/s4/summary/molecular?term=TMEM261&classification=9606&tid=nameOrgENSG00000137038. 
  10. ↑ "Phobius: A combined transmembrane topology and signal peptide predictor". http://phobius.sbc.su.se/. 
  11. ↑ "Q96GE9 - TM261_HUMAN". UniProt Consortium. https://www.uniprot.org/uniprot/Q96GE9. 
  12. ↑ 12.0 12.1 "Vega: Transcript: C9orf123-003". http://vega.sanger.ac.uk/Homo_sapiens/Transcript/ProteinSummary?db=core;g=OTTHUMG00000019539;r=9:7796490-7888380;t=OTTHUMT00000051705. 
  13. ↑ "PHYRE: Protein Homology/analogY Recognition Engine". http://www.sbg.bio.ic.ac.uk/phyre2/html/page.cgi?id=index. 
  14. ↑ "Protein structure prediction on the Web: a case study using the Phyre server". Nature Protocols 4 (3): 363–371. 2009. doi:10.1038/nprot.2009.2. PMID 19247286. 
  15. ↑ 15.0 15.1 "ClustalW". http://workbench.sdsc.edu/. 
  16. ↑ 16.0 16.1 "CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice". Nucleic Acids Research 22 (22): 4673–4680. November 1994. doi:10.1093/nar/22.22.4673. PMID 7984417. 
  17. ↑ "Myristoylation : Proteins Post-translational Modifications". University of Turin. http://flipper.diff.org/app/pathways/info/4026. 
  18. ↑ Nextprot:TMEM261 » Transmembrane protein 261 (Report). doi:10.25504/fairsharing.ceeffa. 
  19. ↑ "Changes in differential gene expression because of warm ischemia time of radical prostatectomy specimens". The American Journal of Pathology 161 (5): 1743–1748. November 2002. doi:10.1016/S0002-9440(10)64451-3. PMID 12414521. 
  20. ↑ "An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence". BMC Genomics 12 (355). July 2011. doi:10.1186/1471-2164-12-355. PMID 21740549. 
  21. ↑ "c9orf123 protein (Homo Sapiens)- STRING Network View". http://string-db.org/newstring_cgi/show_input_page.pl?UserId=65EMVhw9LAhY&sessionId=N5_gHtjz1Wbz. 
  22. ↑ "Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein". The Journal of Biological Chemistry 286 (39): 34088–34100. September 2011. doi:10.1074/jbc.M111.243907. PMID 21832049. 
  23. ↑ "High-Throughput Proteomic Mapping of Human Interaction Networks via Affinity-Purification Mass Spectrometry (Pre-Publication)". Pre-Publication. 2014. http://thebiogrid.org/166968/publication/high-throughput-proteomic-mapping-of-human-interaction-networks-via-affinity-purification-mass-spectrometry.html. 
  24. ↑ "A protein interaction framework for human mRNA degradation". Genome Research 14 (7): 1315–1323. July 2004. doi:10.1101/gr.2122004. PMID 15231747. 
  25. ↑ "9ORF123 chromosome 9 open reading frame 123". TyersLab. http://thebiogrid.org/124777/summary/homo-sapiens/c9orf123.html. 
  26. ↑ 26.0 26.1 26.2 "Definition, conservation and epigenetics of housekeeping and tissue-enriched genes". BMC Genomics 10: 269. 2009. doi:10.1186/1471-2164-10-269. PMID 19534766. 
  27. ↑ "GeneCards:MEF2C Gene". https://www.genecards.org/cgi-bin/carddisp.pl?gene=MEF2C&search=b74dc542dd9d720d31835d8b921cab5f. 
  28. ↑ "Global regulation of erythroid gene expression by transcription factor GATA-1". Blood 104 (10): 3136–3147. November 2004. doi:10.1182/blood-2004-04-1603. PMID 15297311. 
  29. ↑ "Global gene expression analysis of human erythroid progenitors". Blood 117 (13): e96–108. March 2011. doi:10.1182/blood-2010-07-290825. PMID 21270440. 
  30. ↑ "Genomatics- NGS Data Analysis and Personalised Medicine". Genomatix Software GmbH. https://www.genomatix.de/. 
  31. ↑ 31.0 31.1 31.2 "The Human Protein Atlas:TMEM261". http://www.proteinatlas.org/ENSG00000137038-TMEM261/tissue. 
  32. ↑ "EST profile: TMEM261". UniGene. National Library of Medicine. https://www.ncbi.nlm.nih.gov/UniGene/clust.cgi?UGID=132138&TAXID=9606&SEARCH=c9orf123. 
  33. ↑ 33.0 33.1 "Identification and functional analysis of 9p24 amplified genes in human breast cancer". Oncogene 31 (3): 333–341. January 2012. doi:10.1038/onc.2011.227. PMID 21666724. 
  34. ↑ "Cross-species comparison of human and mouse intestinal polyps reveals conserved mechanisms in adenomatous polyposis coli (APC)-driven tumorigenesis". The American Journal of Pathology 172 (5): 1363–1380. May 2008. doi:10.2353/ajpath.2008.070851. PMID 18403596. 
  35. ↑ "Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma". Blood 123 (13): 2062–2065. March 2014. doi:10.1182/blood-2013-10-535443. PMID 24497532. 
  36. ↑ "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. October 2010. doi:10.1182/blood-2010-05-282780. PMID 20628145. 
  37. ↑ 37.0 37.1 "NCBI BLAST:Basic Local Alignment Search Tool". https://blast.ncbi.nlm.nih.gov/Blast.cgi. 
  38. ↑ "TimeTree: a public knowledge-base of divergence times among organisms". Bioinformatics (Oxford, England) 22 (23): 2971–2972. December 2006. doi:10.1093/bioinformatics/btl505. PMID 17021158. http://kumarlab.net/pdf_new/HedgesKumar06.pdf. 

Further reading

  • "Protein tyrosine phosphatases: from genes, to function, to disease". Nature Reviews. Molecular Cell Biology 7 (11): 833–846. November 2006. doi:10.1038/nrm2039. PMID 17057753. 
  • "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. July 2008. doi:10.1016/j.ccr.2008.05.016. PMID 18598941. 



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