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Chromosome 9 Open Reading Frame 40

From EverybodyWiki Bios & Wiki




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Chromosome 9 Open Reading Frame 40 (C9orf40) is a protein that, in Homo sapiens, is encoded by the c9orf40 gene.[1]. Within the cell, the C9orf40 protein is localized to the nucleus, cytoplasm, and centrosome[2] where it is believed to play a role in cellular senescence[3][4]

Gene[edit]

C9orf40 is a protein-encoding gene located on the long arm of chromosome 9 (9q21.13)[5] of the human genome[6] that contains 2 exons and spans 6,330 bases on the minus strand.

Annotated conceptual Translation of the human c9orf40 gene.[7]

RNA[edit]

Gene Expression[edit]

C9orf40 mRNA is ubiquitously expressed at medium levels[8], with peaks in the digestive tract. Like most other genes,[9] c9orf40 sees its highest expression in the testes.

Transcripts[edit]

Human c9orf40 has only one form, using both of its exons which encode a 2,351 base mRNA.[8]

Protein[edit]

The protein encoded by human c9orf40 consists of 194 amino acids and has an estimated molecular weight of 21.1 kDa.[10] With a predicted isoelectric point of 4.9, the human c9orf40 protein is fairly acidic, however, this is not conserved across orthologs. There are no prominent repeats, and the protein only differs from average composition with below-normal levels of isoleucine and tyrosine, above-normal levels of glycine and significantly above-average levels of proline, which in series indicates the presence of polyproline helices.[11][12]

Protein Level Regulation[edit]

Protein abundance of human c9orf40 is not ubiquitous; of available tissue level immunohistochemistry data, the strongest staining was observed in glandular cells of the colon and parathyroid gland, tubules in the kidney and germinal center cells in lymph nodes.[13] The c9orf40 protein contains nuclear localization signals,[14][15] and subcellular immunofluorescent staining using a c9orf40 polyclonal antibody in the U-251MG cell line shows localization in the cytoplasm, centrosome, and nucleus (with exclusion from the nucleoli).[16]

Domains[edit]

Within c9orf40, there is one notable domain of a known function[6]. That is the WWBD&DB or "Putative WW-Binding Domain and Destruction Box" which ranges Q149:E189 and contains a short conserved region that acts as a destruction box having a RxxLxxI sequence motif[17]. WW domains bind to proline-rich protein and peptide ligands.[18]

WWBD&DB of c9orf40 Logo. Made by Web Logo of UC Berkeley[19]. This logo is made using the sequence between amino acids 149 and 189 in the Human protein and its orthologs marking the region of the WW-Binding Domain & Destruction Box. The size of each letter represents how common it is in that position.

Post Translational Modifications[edit]

There is a high level of overlap between phosphorylation sites[20][21] on the human c9orf40 protein and predicted YinOYang glycosylation sites[21], most of which are located centrally in the AA sequence and conserved across orthologs. Additionally, a shared Acetylation[20] and Ubiquitylation[20] site is found near the N-Terminus.

Post-translational modification protein diagram. WWBD&DB: WW Binding Domain and Destruction Box. P= Phosphorylation site[20][22] Light pink indicates that the phosphorylation site is not conserved in mice. A= Acetylation[20] U= Ubiquitylation[20] *= YinOYang site[21]

Structure[edit]

Confidence of available predicted structures for human c9orf40 protein remains low for many of its regions. There are no major areas of unified charge or hydrophobicity.

c9orf40 Protein Structure: Predicted model of the tertiary structure of human c9orf40 protein with polyproline helices marked, and WWBD&DB identified.[23][24]

Function[edit]

This protein is believed to play a role in cellular senescence.[25][26] This is senescence is thought to be through a mechanism of action where c9orf40 activates p21,therefore, inhibiting the proliferation by the CDK or proliferating cell nuclear antigen (PCNA) signaling pathway thereby promoting apoptosis by the caspase-3 signaling pathway.[25][27][28]

Homology/ Evolution[edit]

Homology[edit]

The protein c9orf40 does not have currently known paralogs within the human genome.[29] Orthologs are present in most Jawed Vertebrates.

Ortholog Table of c9orf40 proteins. Sorted by Taxon, Date of divergence, and approximate Percent Similarity.
Class Genus and Species Common name Taxon DoD (MYA)[30] Accession # from NCBI gene[31] Length (AA) Percent Identity[32] Percent Similarity[32]
Mamalia Homo sapiens Human Primata 0 NP_060468.2 194 100 100
Gorilla gorilla Gorilla Primata 8.6 XP_030870662.1 194 99.5 99.5
Camelus ferus Camel Even-toed ungulates 94 XP_032333750.1 195 77.4 82.6
Mus musculus House Mouse Rodentia 87 NP_001361059.1 163 53.1 63.9
Reptilia Mauremys mutica Yellow Pond Turtle Testudines 319 XP_044876188.1 179 37.4 46.9
Chelonoidis abingdonii Pinta Island Tortoise Testudines 319 XP_032642932.1 179 36.3 45.8
Varanus komodoensis komodo dragon Squamata 319 XP_044302814.1 185 25.9 37.1
Aves Accipiter gentilis Northern goshawk Accipitriformes 319 XP_049651473.1 161 36.5 45.2
Falco naumanni Lesser Kestrel Falconiformes 319 XP_040435111.1 162 34.5 44.5
Gallus gallus Chicken Galliformes 319 XP_004949223.3 162 33 42
Parus major Great Tit Passeriformes 319 XP_015507986.1 186 29.4 37.9
Coturnix japonica Japanese Quail Galliformes 319 XP_032297374.1 186 27.3 36
Pyrgilauda ruficollis Rufous-necked snowfinch Passeriformes 319 XP_041345416.1 170 28.8 36
Amphibia Pleurodeles waltl Iberian Ribbed Newt Urodela 353 KAJ1206789 173 34.3 42.8
Engystomops pustulosus Tungara Frog Anura 353 KAG8595788.1 139 27.8 41.8
Rana temporaria Common Frog Anura 353 XP_040212144.1 129 25.6 35.7
Rhinatrema bivittatum Two lined Caecillians Apoda 353 XP_040212144.1 150 25.9 34.3
Geotrypetes seraphini Gaboon caecilian Apoda 353 XP_033812609.1 149 23.4 35.3
Microcaecilia unicolor Apoda 353 XP_030048216.1 154 21 31.4
Sarcopterigii Latimeria chalumnae West Indian Ocean Coelacanth Coelacanthiformes 414 XP_006005353.1 189 29.1 39.5
Actinopterigii Salarias fasciatus Lawnmower Blenny Perciformes 431 XP_029960337.1 186 29.1 41.7
Erpetoichthys calabaricus Reedfish Polypteriformes 431 XP_028658189.1 163 24.4 37.6
Oreochromis niloticus Nile Tilapia Perciformes 431 XP_003445575.1 177 26 36.5
Anguilla Anguilla European Eel Anguilliformes 431 XP_035235206 200 23.5 34.6
Chondrichthyes Stegostoma fasciatum Zebra Shark Orectolobiformes 464 XP_048383253.1 173 28.5 39.3
Chiloscyllium plagiosum White Spotted Bamboo shark Orectolobiformes 464 XP_043568168.1 164 28.2 37.9
Pristis pectinata Smalltooth Sawfish Pristiformes 464 XP_051876118.1 166 25.4 37.6

Conservation[edit]

The c9orf40 protein has sporadic conservation among vertebrates, with particular notability around the W-W binding domain and destruction box as well as the N-terminus of the AA sequences.

C9orf40 Ortholog Alignment: Multiple Sequence Alignment containing select mammal and Reptile orthologs of Human c9orf40 protein.[33]

Evolutionary History[edit]

C9orf40 appeared approximately 460 million years ago in sharks[34]. Notably, this gene is fairly quickly diverging, about 3x as fast as Cytochrome C, and just below the rate of Fibrinogen Alpha. With the farthest back known ancestors being jawed vertebrates, there is no evidence of this gene existing prior to the evolutionary development of jaws.

Phylogenetic Tree of c9orf40[35][36][37][38][39][40][41] based on the relationship of orthologous protein sequences.

References[edit]

  1. ↑ "UniProt". www.uniprot.org. Retrieved 2023-07-03.
  2. ↑ "Tissue expression of C9orf40 - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2023-07-03.
  3. ↑ Avelar, Roberto A.; Ortega, Javier Gómez; Tacutu, Robi; Tyler, Eleanor J.; Bennett, Dominic; Binetti, Paolo; Budovsky, Arie; Chatsirisupachai, Kasit; Johnson, Emily; Murray, Alex; Shields, Samuel; Tejada-Martinez, Daniela; Thornton, Daniel; Fraifeld, Vadim E.; Bishop, Cleo L. (December 2020). "A multidimensional systems biology analysis of cellular senescence in aging and disease". Genome Biology. 21 (1): 91. doi:10.1186/s13059-020-01990-9. ISSN 1474-760X. PMC 7333371 Check |pmc= value (help). PMID 32264951 Check |pmid= value (help).
  4. ↑ Huang, Yutao; Gao, Xiangyu; Yang, Erwan; Yue, Kangyi; Cao, Yuan; Zhao, Boyan; Zhang, Haofuzi; Dai, Shuhui; Zhang, Lei; Luo, Peng; Jiang, Xiaofan (2022-02-22). "Top-down stepwise refinement identifies coding and noncoding RNA-associated epigenetic regulatory maps in malignant glioma". Journal of Cellular and Molecular Medicine. 26 (8): 2230–2250. doi:10.1111/jcmm.17244. ISSN 1582-1838. PMC 8995455 Check |pmc= value (help). PMID 35194922 Check |pmid= value (help).
  5. ↑ "C9Orf40". GeneCards. 2023-04-21.
  6. ↑ 6.0 6.1 "C9orf40 chromosome 9 open reading frame 40 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-10-03.
  7. ↑ "Six-Frame Translation". www.bioline.com. Retrieved 2022-12-16.
  8. ↑ 8.0 8.1 "C9orf40 chromosome 9 open reading frame 40 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-05-04.
  9. ↑ Ahn, Jinsoo; Park, Yoo-Jin; Chen, Paula; Lee, Tae Jin; Jeon, Young-Jun; Croce, Carlo M.; Suh, Yeunsu; Hwang, Seongsoo; Kwon, Woo-Sung; Pang, Myung-Geol; Kim, Cheorl-Ho; Lee, Sang Suk; Lee, Kichoon (2017-04-17). Qiu, Gao-Feng, ed. "Comparative expression profiling of testis-enriched genes regulated during the development of spermatogonial cells". PLOS ONE. 12 (4): e0175787. Bibcode:2017PLoSO..1275787A. doi:10.1371/journal.pone.0175787. ISSN 1932-6203. PMC 5393594. PMID 28414809.
  10. ↑ "uncharacterized protein C9orf40 [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-10-03.
  11. ↑ Morgan, Alexander A.; Rubenstein, Edward (2013-01-25). Casarini, Dulce Elena, ed. "Proline: The Distribution, Frequency, Positioning, and Common Functional Roles of Proline and Polyproline Sequences in the Human Proteome". PLOS ONE. 8 (1): e53785. Bibcode:2013PLoSO...853785M. doi:10.1371/journal.pone.0053785. ISSN 1932-6203. PMC 3556072. PMID 23372670.
  12. ↑ Adzhubei, Alexei A.; Sternberg, Michael J.E.; Makarov, Alexander A. (June 2013). "Polyproline-II Helix in Proteins: Structure and Function". Journal of Molecular Biology. 425 (12): 2100–2132. doi:10.1016/j.jmb.2013.03.018. PMID 23507311.
  13. ↑ "Tissue expression of C9orf40 - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2022-12-16.
  14. ↑ DeepLoc 2.0: multi-label subcellular localization prediction using protein language models. Vineet Thumuluri, Jose Juan Almagro Armenteros, Alexander Rosenberg Johansen, Henrik Nielsen, Ole Winther. Nucleic Acids Research, Web server issue 2022.
  15. ↑ "PSORT II Prediction". psort.hgc.jp. Retrieved 2022-12-16.
  16. ↑ "C9orf40 Polyclonal Antibody (PA5-59900)". www.thermofisher.com. Retrieved 2022-12-08.
  17. ↑ "InterPro". www.ebi.ac.uk. Retrieved 2023-07-03.
  18. ↑ Hesselberth, Jay R; Miller, John P; Golob, Anna; Stajich, Jason E; Michaud, Gregory A; Fields, Stanley (2006). "Comparative analysis of Saccharomyces cerevisiae WW domains and their interacting proteins". Genome Biology. 7 (4): R30. doi:10.1186/gb-2006-7-4-r30. PMC 1557994. PMID 16606443.
  19. ↑ "WebLogo - Create Sequence Logos". weblogo.berkeley.edu. Retrieved 2022-12-16.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 "C9orf40 (human)". www.phosphosite.org. Retrieved 2022-12-16.
  21. ↑ 21.0 21.1 21.2 "Services". www.healthtech.dtu.dk. Retrieved 2022-12-16.
  22. ↑ "Services". www.healthtech.dtu.dk. Retrieved 2022-12-16.
  23. ↑ Jumper, John; Evans, Richard; Pritzel, Alexander; Green, Tim; Figurnov, Michael; Ronneberger, Olaf; Tunyasuvunakool, Kathryn; Bates, Russ; Žídek, Augustin; Potapenko, Anna; Bridgland, Alex; Meyer, Clemens; Kohl, Simon A. A.; Ballard, Andrew J.; Cowie, Andrew (2021-08-26). "Highly accurate protein structure prediction with AlphaFold". Nature. 596 (7873): 583–589. Bibcode:2021Natur.596..583J. doi:10.1038/s41586-021-03819-2. ISSN 0028-0836. PMC 8371605 Check |pmc= value (help). PMID 34265844 Check |pmid= value (help).
  24. ↑ Mihaly Varadi, Stephen Anyango, Mandar Deshpande, Sreenath Nair, Cindy Natassia, Galabina Yordanova, David Yuan, Oana Stroe, Gemma Wood, Agata Laydon, Augustin Žídek, Tim Green, Kathryn Tunyasuvunakool, Stig Petersen, John Jumper, Ellen Clancy, Richard Green, Ankur Vora, Mira Lutfi, Michael Figurnov, Andrew Cowie, Nicole Hobbs, Pushmeet Kohli, Gerard Kleywegt, Ewan Birney, Demis Hassabis, Sameer Velankar, AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models, Nucleic Acids Research, Volume 50, Issue D1, 7 January 2022, Pages D439–D444, doi:10.1093/nar/gkab1061
  25. ↑ 25.0 25.1 Avelar, Roberto A.; Ortega, Javier Gómez; Tacutu, Robi; Tyler, Eleanor J.; Bennett, Dominic; Binetti, Paolo; Budovsky, Arie; Chatsirisupachai, Kasit; Johnson, Emily; Murray, Alex; Shields, Samuel; Tejada-Martinez, Daniela; Thornton, Daniel; Fraifeld, Vadim E.; Bishop, Cleo L. (2020-04-07). "A multidimensional systems biology analysis of cellular senescence in aging and disease". Genome Biology. 21 (1): 91. doi:10.1186/s13059-020-01990-9. ISSN 1474-760X. PMC 7333371 Check |pmc= value (help). PMID 32264951 Check |pmid= value (help).
  26. ↑ Huang, Yutao; Gao, Xiangyu; Yang, Erwan; Yue, Kangyi; Cao, Yuan; Zhao, Boyan; Zhang, Haofuzi; Dai, Shuhui; Zhang, Lei; Luo, Peng; Jiang, Xiaofan (April 2022). "Top-down stepwise refinement identifies coding and noncoding RNA-associated epigenetic regulatory maps in malignant glioma". Journal of Cellular and Molecular Medicine. 26 (8): 2230–2250. doi:10.1111/jcmm.17244. ISSN 1582-1838. PMC 8995455 Check |pmc= value (help). PMID 35194922 Check |pmid= value (help).
  27. ↑ Luo, Y., Hurwitz, J., & Massagué, J. (1995). Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature, 375(6527), 159-161.
  28. ↑ Chen J, Saha P, Kornbluth S, Dynlacht BD, Dutta A. Cyclin‐binding motifs are essential for the function of p21CIP1. Mol Cell Biol. 1996;16(9):4673–4682.
  29. ↑ "Protein BLAST: search protein databases using a protein query". blast.ncbi.nlm.nih.gov. Retrieved 2022-10-24.
  30. ↑ "TimeTree :: The Timescale of Life". timetree.org. Retrieved 2022-12-08.
  31. ↑ "Home - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-08.
  32. ↑ 32.0 32.1 "EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI". www.ebi.ac.uk. Retrieved 2022-12-08.
  33. ↑ Sievers, Fabian; Wilm, Andreas; Dineen, David; Gibson, Toby J; Karplus, Kevin; Li, Weizhong; Lopez, Rodrigo; McWilliam, Hamish; Remmert, Michael; Söding, Johannes; Thompson, Julie D; Higgins, Desmond G (January 2011). "Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega". Molecular Systems Biology. 7 (1): 539. doi:10.1038/msb.2011.75. ISSN 1744-4292. PMC 3261699. PMID 21988835.
  34. ↑ "Shark evolution: a 450 million year timeline". www.nhm.ac.uk. Retrieved 2023-07-03.
  35. ↑ "Phylogeny.fr: "One Click" Mode". www.phylogeny.fr. Retrieved 2022-12-16.
  36. ↑ Dereeper, Alexis; Audic, Stephane; Claverie, Jean-Michel; Blanc, Guillaume (2010-01-12). "BLAST-EXPLORER helps you building datasets for phylogenetic analysis". BMC Evolutionary Biology. 10 (1): 8. Bibcode:2010BMCEE..10....8D. doi:10.1186/1471-2148-10-8. ISSN 1471-2148. PMC 2821324. PMID 20067610.
  37. ↑ Dereeper A.*, Guignon V.*, Blanc G., Audic S., Buffet S., Chevenet F., Dufayard J.F., Guindon S., Lefort V., Lescot M., Claverie J.M., Gascuel O. Phylogeny.fr: robust phylogenetic analysis for the non-specialist. Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W465-9. Epub 2008 Apr 19. (PubMed) *: joint first authors
  38. ↑ Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004, Mar 19;32(5):1792-7. (PubMed)
  39. ↑ Castresana J. Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis. Mol Biol Evol. 2000, Apr;17(4):540-52. (PubMed)
  40. ↑ Guindon S., Gascuel O. A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst Biol. 2003, Oct;52(5):696-704. (PubMed)
  41. ↑ Chevenet F., Brun C., Banuls AL., Jacq B., Chisten R. TreeDyn: towards dynamic graphics and annotations for analyses of trees. BMC Bioinformatics. 2006, Oct 10;7:439. (PubMed)


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