C5orf24 Explained

C5orf24 (chromosome 5 open reading frame 24) is a protein encoded by the C5orf24 gene (5q31.1) in humans.[1] C5orf24 is primarily localized to the nucleus and is highly conserved with orthologs in mammals, birds, reptiles, amphibians, and fish.[2]

Gene

Human C5orf24 is a protein-coding gene 26,133 base pairs long (chr5:134,833,603-134,859,735) composed of two exons and one intron at locus 5q31.1 oriented on the plus strand.[3] [4] [5] Alternate names for the gene are FLJ37562 and LOC134553.[6] [7] Genes neighboring C5orf24 include DDX46, RPL34P13, and TXNDC15. Some transcription factors predicted to bind to conserved sites on the promoter region (GXP_7545710) are NRF1, E2F, ZF5, and AHR.[8]

Transcripts

Transcript VariantLength (nt)Protein IsoformLength (aa)
1 (NM_001135586.1)50831 (NP_001129058.1)188
2 (NM_152409.3)48961 (NP_689622.2)188
3 (NM_001300894.2)30542 (NP_001287823.1)155

The human C5orf24 gene has three mRNA transcript variants.[9] Both transcript variant 1 and 2 encode protein isoform 1 which is 188 amino acids in length.[10] [11] Transcript variant 1 is the longest and highest quality transcript (5083 nucleotides) with transcript variant 2 (4896 nucleotides) having a smaller 5' UTR region. Transcript variant 3 lacks an internal segment resulting in an alternate translational stop codon making it is the shortest variant (3054 nucleotides) encoding the smaller protein isoform 2 which is 155 amino acids in length.[12]

Protein

Isoform 1 of the UPF0461 protein C5orf24 is 188 amino acids long encoded by exon 2. It contains two disordered regions at the amino acid positions 1-20 and 79-142, respectively. The second disordered region contains a series of internal repeats.[13] [14] The human precursor protein is predicted to be 20.1 kDa with an isoelectric point of approximately 10.[15] Immunoblotting demonstrated the experimental molecular-weight to be about 25 kDa.[16] Three experimental phosphorylation sites have been reported at Ser37,[17] Ser121,[18] and Ser180 along with evidence for a ubiquitination site at Lys146.[19] [20] [21] A conserved nuclear localization signal at amino acid positions 79 – 83 (KKKK) was corroborated by immunofluorescence experiments using anti-C5orf24 antibodies depicting localization to the nucleoplasm.[22] [23] Affinity chromatography and anti tag coimmunoprecipitation experiments showed C5orf24 likely interacts with multiple other proteins including STK11, CAB39, LYK5, PKNOX1, and PBX1.[24] [25]

Evolutionary history

Orthologs

The C5orf24 protein is not present in plants or fungus but orthologs have been found in mammals, birds, reptiles, amphibians, as well as bony fish (Osteichthyes) and cartilaginous fish (Chondrichthyes). There is evidence for an orthologous domain in jawless fishes (Agnatha) and invertebrates. Comparison of m values (corrected rate of divergence) between C5orf24 (NP_001129058.1), Cytochrome c (NP_061820.1) which has a slow rate of evolution,[26] and Fibrinogen alpha (NP_000499.1) which has a fast rate of evolution[27] demonstrated this protein evolved at fairly slow rate especially when fish sequences are excluded.[28] [29] [30]

C5orf24Scientific NameCommon NameTaxonomic GroupMedian Date of Divergence (MYA)Accession NumberSequence Length (aa)Query CoverSequence Identity
MammalsHomo sapiensHumanPrimates0NP_001129058.1188100%100%
Cavia porcellusGuinea PigRodentia89XP_005005246.1188100%98.4%
Ursus maritimusPolar BearCarnivora94XP_008689817.1188100%97.9%
Trichechus manatus latirostrisFlorida ManateeSirenia102XP_004384765.1188100%95.7%
Ornithorhynchus anatinusPlatypusMonotremata180XP_007669207.1188100%82.4%
BirdsCalypte annaAnna's HummingbirdApodiformes318XP_030314921.1188100%86.2%
Strigops habroptilaKākāpōPsittaciformes318XP_030360294.1188100%85.1%
ReptilesPelodiscus sinensisChinese Softshell TurtleTestudines318XP_006116108.1188100%85.1%
Python bivittatusBurmese pythonSquamata318XP_007421938.1188100%78.7%
AmphibiansRhinatrema bivittatumTwo-Lined CaecilianGymnophiona 352XP_029439506.1188100%75.5%
Xenopus tropicalisTropical Clawed FrogAnura 352NP_001072358.1186100%70.7%
FishesEsox LuciusNorthern PikeOsteichtyes 433XP_019903474.2204100%56.5%
Scyliorhinus canicularSmall-Spotted CatsharkChondrichthyes 465XP_038651786.119396%53.8%

Paralogs

The C5orf24 gene has no paralogs.

Conservation

Multiple sequence alignments revealed the C5orf24 protein has been highly conserved and likely originated in cartilaginous fishes nearly 465 million years ago.[31] [32] A series of internal repeats in the second disordered region were additionally identified in proteins found within jawless fishes and invertebrates, suggesting an orthologous domain began even further back in evolutionary history.

Clinical significance

Expression

C5orf24 is ubiquitously expressed with limited tissue variability.[33] Microarray-assessed tissue expression patterns show C5orf24 levels decreasing in pro-inflammatory environments such as in patients with tibial muscular dystrophy[34] and children with obesity.[35]

Genotype-phenotype correlations

While this gene has yet to be well understood by the scientific community, some genotype-phenotype correlations have been established including the upregulation of C5orf24 in individuals with PTSD and downregulation in those with improved symptoms,[36] a linear correlation between methylation levels of C5orf24 GC sites to negative affect scores in drug addicts,[37] as well as GWAS studies demonstrating SNPs in C5orf24 to be associated with Parkinson's disease in the Chinese Han population[38] and Crohn's disease.[39]

Notes and References

  1. Web site: UPF0461 protein C5orf24 isoform 1 [Homo sapiens]]. live. 16 December 2021. NCBI Protein. https://web.archive.org/web/20211017232649/https://www.ncbi.nlm.nih.gov/protein/NP_001129058.1 . 2021-10-17 .
  2. Web site: C5orf24. live. 15 November 2021. PSORT II Prediction. https://web.archive.org/web/20031214095645/http://psort.hgc.jp:80/form2.html . 2003-12-14 .
  3. Web site: C5orf24 chromosome 5 open reading frame 24 [Homo sapiens (human) ]]. 25 September 2021. NCBI Gene.
  4. Web site: Homo sapiens gene C5orf24, encoding chromosome 5 open reading frame 24. live. 18 September 2021. NCBI AceView. https://web.archive.org/web/20011212080517/http://www.ncbi.nlm.nih.gov:80/IEB/Research/Acembly/ . 2001-12-12 .
  5. Web site: C5orf24 Gene - GeneCards CE024 Protein CE024 Antibody. 2021-12-18. www.genecards.org.
  6. Web site: Gene: C5orf24 (ENSG00000181904) - Summary - Homo_sapiens - Ensembl genome browser 105. 2021-12-17. www.ensembl.org.
  7. Web site: Gene symbol report HUGO Gene Nomenclature Committee. 2021-12-17. www.genenames.org.
  8. Web site: MatInspector: Search for transcription factor binding sites. live. 20 November 2021. genomatix. https://web.archive.org/web/20020812010040/http://www.genomatix.de:80/online_help/help_matinspector/matinspector_help.html . 2002-08-12 .
  9. Web site: C5orf24 (Homo sapiens chromosome 5 open reading frame 24) transcript variant 1 mRNA. live. 16 September 2021. UCSC Genome Browser. https://web.archive.org/web/20020207214245/http://genome.ucsc.edu:80/cgi-bin/hgGateway . 2002-02-07 .
  10. Homo sapiens chromosome 5 open reading frame 24 (C5orf24), transcript variant 1, mRNA. NCBI Gene. 18 June 2021.
  11. Homo sapiens chromosome 5 open reading frame 24 (C5orf24), transcript variant 2, mRNA. NCBI Gene. 18 June 2021.
  12. Homo sapiens chromosome 5 open reading frame 24 (C5orf24), transcript variant 3, mRNA. NCBI Gene. 27 June 2021.
  13. Web site: Dotlet JS. 2021-12-17. dotlet.vital-it.ch.
  14. Web site: SAPS < Sequence Statistics < EMBL-EBI. 2021-12-17. www.ebi.ac.uk.
  15. Web site: Compute pI/Mw tool. live. 2 December 2021. ExPASy. https://web.archive.org/web/20110704185433/http://web.expasy.org:80/compute_pi/ . 2011-07-04 .
  16. Web site: Anti-C5orf24 (61-75) antibody produced in rabbit. live. MilliporeSigma. https://web.archive.org/web/20211216233306/https://www.sigmaaldrich.com/US/en/product/sigma/sab1103592 . 2021-12-16 .
  17. Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S . Toward a comprehensive characterization of a human cancer cell phosphoproteome . Journal of Proteome Research . 12 . 1 . 260–271 . January 2013 . 23186163 . 10.1021/pr300630k .
  18. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ . ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage . Science . 316 . 5828 . 1160–1166 . May 2007 . 17525332 . 10.1126/science.1140321 . 16648052 . 2007Sci...316.1160M .
  19. Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C . A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles . Molecular & Cellular Proteomics . 10 . 10 . M111.013284 . October 2011 . 21890473 . 3205876 . 10.1074/mcp.M111.013284 . free .
  20. Akimov V, Barrio-Hernandez I, Hansen SV, Hallenborg P, Pedersen AK, Bekker-Jensen DB, Puglia M, Christensen SD, Vanselow JT, Nielsen MM, Kratchmarova I, Kelstrup CD, Olsen JV, Blagoev B . UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites . Nature Structural & Molecular Biology . 25 . 7 . 631–640 . July 2018 . 29967540 . 10.1038/s41594-018-0084-y . 49559977 .
  21. Web site: UPF0461 protein C5orf24. live. 15 November 2021. PhosphoSitePlus. https://web.archive.org/web/20211216215637/https://www.phosphosite.org/proteinAction.action?id=11980&showAllSites=true . 2021-12-16 .
  22. Web site: 2 October 2021. Standard Protein BLAST (Basic Local Alignment Search Tool). live. NCBI. https://web.archive.org/web/20110408123221/http://blast.ncbi.nlm.nih.gov:80/Blast.cgi?PAGE=Proteins . 2011-04-08 .
  23. Web site: Anti-C5orf24 antibody produced in rabbit. live. MilliporeSigma. https://web.archive.org/web/20211216215634/https://www.sigmaaldrich.com/US/en/product/sigma/hpa062502 . 2021-12-16 .
  24. Huttlin EL, Bruckner RJ, Paulo JA, Cannon JR, Ting L, Baltier K, Colby G, Gebreab F, Gygi MP, Parzen H, Szpyt J, Tam S, Zarraga G, Pontano-Vaites L, Swarup S, White AE, Schweppe DK, Rad R, Erickson BK, Obar RA, Guruharsha KG, Li K, Artavanis-Tsakonas S, Gygi SP, Harper JW . Architecture of the human interactome defines protein communities and disease networks . Nature . 545 . 7655 . 505–509 . May 2017 . 28514442 . 5531611 . 10.1038/nature22366 . 2017Natur.545..505H .
  25. Web site: C5orf24. 20 September 2021. STRING.
  26. Pierron D, Wildman DE, Hüttemann M, Markondapatnaikuni GC, Aras S, Grossman LI . Cytochrome c oxidase: evolution of control via nuclear subunit addition . Biochimica et Biophysica Acta (BBA) - Bioenergetics . 1817 . 4 . 590–597 . April 2012 . 21802404 . 10.1016/j.bbabio.2011.07.007 . 3923406 .
  27. 10.2307/2412963. 2412963. Mammalian Phylogeny Based on Fibrinopeptide Amino Acid Sequences. O'Neil. P. B.. Doolittle. R. F.. Systematic Zoology. 1973. 22. 4. 590–595.
  28. Web site: TimeTree :: The Timescale of Life. 2021-12-17. www.timetree.org.
  29. Web site: cytochrome c [Homo sapiens]]. live. 10 December 2020. NCBI Protein. https://web.archive.org/web/20110810170925/http://www.ncbi.nlm.nih.gov:80/protein/NP_061820.1 . 2011-08-10 .
  30. Web site: fibrinogen alpha chain isoform alpha-E preproprotein [Homo sapiens]]. live. 10 December 2021. NCBI Protein. https://web.archive.org/web/20160826061710/http://www.ncbi.nlm.nih.gov/protein/NP_000499 . 2016-08-26 .
  31. Web site: EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI. 2021-12-17. www.ebi.ac.uk.
  32. Web site: Vital-IT - Competence Centre in Bioinformatics and Computational Biology. 2021-12-17. www.vital-it.ch.
  33. Web site: UPF0461 protein C5orf24 homolog. live. GENEPAINT. https://web.archive.org/web/20211217193703/https://gp3.mpg.de/results/c5orf24 . 2021-12-17 .
  34. Screen M, Raheem O, Holmlund-Hampf J, Jonson PH, Huovinen S, Hackman P, Udd B . Gene expression profiling in tibial muscular dystrophy reveals unfolded protein response and altered autophagy . PLOS ONE . 9 . 3 . e90819 . 2014 . 24618559 . 3949689 . 10.1371/journal.pone.0090819 . 2014PLoSO...990819S . free .
  35. Aguilera CM, Gomez-Llorente C, Tofe I, Gil-Campos M, Cañete R, Gil Á . Genome-wide expression in visceral adipose tissue from obese prepubertal children . International Journal of Molecular Sciences . 16 . 4 . 7723–7737 . April 2015 . 25856673 . 4425045 . 10.3390/ijms16047723 . free .
  36. Rusch HL, Robinson J, Yun S, Osier ND, Martin C, Brewin CR, Gill JM . Gene expression differences in PTSD are uniquely related to the intrusion symptom cluster: A transcriptome-wide analysis in military service members . Brain, Behavior, and Immunity . 80 . 904–908 . August 2019 . 31039430 . 6752960 . 10.1016/j.bbi.2019.04.039 .
  37. Lax E, Warhaftig G, Ohana D, Maayan R, Delayahu Y, Roska P, Ponizovsky AM, Weizman A, Yadid G, Szyf M . A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention . Frontiers in Molecular Neuroscience . 11 . 322 . 2018 . 30250424 . 6139343 . 10.3389/fnmol.2018.00322 . free .
  38. Fan L, Shi C, Hu X, Zhang Z, Zheng H, Luo H, Fan Y, Zhang S, Hu Z, Yang J, Mao C, Xu Y . Analysis of 12 GWAS-Linked Loci With Parkinson's Disease in the Chinese Han Population . Frontiers in Neurology . 12 . 623913 . 2021 . 33897588 . 8058430 . 10.3389/fneur.2021.623913 . free .
  39. O'Donnell S, Borowski K, Espin-Garcia O, Milgrom R, Kabakchiev B, Stempak J, Panikkath D, Eksteen B, Xu W, Steinhart AH, Kaplan GG, McGovern DP, Silverberg MS . The Unsolved Link of Genetic Markers and Crohn's Disease Progression: A North American Cohort Experience . Inflammatory Bowel Diseases . 25 . 9 . 1541–1549 . August 2019 . 30801121 . 10.1093/ibd/izz016 .

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