Biology:C12orf66

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C12orf66 is a protein that in humans is encoded by the C12orf66 gene.[1] The C12orf66 protein is one of four proteins in the KICSTOR protein complex which negatively regulates mechanistic target of rapamycin complex 1 (mTORC1) signaling.

Gene

Human C12orf66 transcript variants

C12orf66 is located on the minus strand in the locus 12q14.2.[1] C12orf66 variant 1 is 36 Mbp in length spanning the base pairs 64,186,312 - 64,222,296 on chromosome 12. There are 3 total C12orf66 transcript variants. C12orf66 variant 1 is the longest with 4 exons. C12orf66 variant 2 has a shortened exon 1 and is missing exon 4 compared to variant 1. C12orf66 variant 3 is missing exon 4.[1]

The expression profile for C12orf66 across a variety of tissue samples in the GDS3834 NCBI Geo set. Red bars represent individual expression values and should be considered arbitrary when making comparisons between samples. Blue boxes represent the expression level rank within a single sample and should be used to compare expression levels of the gene between samples.[2]

Expression

In humans, C12orf66 has higher than average expression in a number of tissues such as endocrine glands as well as lymphoid tissues and cells.[2] Additionally, C12orf66 expression is increased in a number of cancers including leukemia, breast cancer, cervical cancer, and a number of gastrointestinal related cancers.[3][4] C12orf66 expression is higher earlier in development. A number of experiments using different human embryonic stem cell lines, oocytes, as well as erythroblasts found C12orf66 expression was increased in these cells earlier in development and expression decreased as these cells became more differentiated.[5][6][7] Additionally, expression of C12orf66 in fetal organs is higher than C12orf66 expression in the same adult organs.[2]

Protein

Predicted human C12orf66 protein structure[8]

The human C12orf66 protein is 446 amino acids in length with a molecular weight of 50kdal .[1][9][10] C12orf66 contains the domain of unknown function 2003 (DUF2003) from amino acids 10-444.[9] The DUF2003 is characterized by a series of alpha helices and beta sheets.[11]

Visual representation of the protein encoded by the human C12orf66 gene with predicted secondary structures and post-translational modification sites
C12orf66 Protein
Property Prediction
Isoelectric Point 9.2[12]
Cellular Location Cytoplasm[12][13][14]
Phosphorylation Sites T236, T282, S417[15][16]
N-Myristoylation Sites G75, G442[15]

Function

C12orf66 is part of a larger protein complex called KICSTOR. KICSTOR is a complex of four proteins coded by the genes KPTN, ITFG2, C12orf66, and SZT2.[10] The KICSTOR complex plays a role in regulating mTORC1 signaling. mTORC1 activates protein translation when the cell has sufficient amounts amino acids and energy. This ensures cell growth and proliferation occurs in ideal cellular environments.[17] KICSTOR recruits the protein complex GATOR1, a negative regulator of mTORC1, to the correct location on the lysosome where mTORC1 signaling occurs.[10] In addition to the localization of GATOR1 to the lysosome, KICSTOR is also necessary for the regulation of mTORC1 signaling by amino acid or glucose deprivation. Normally, amino acid or glucose deprivation inhibits mTORC1 signaling. However, loss of any one protein in the four protein KICSTOR complex resulted in a lack of inhibition of mTORC1 by amino acid or glucose deprivation and increased mTORC1 signaling.[10] Thus, KICSTOR is a negative regulator of mTORC1 signaling that functions by localizing GATOR1 to the lysosomal surface as well inhibiting mTORC1 during periods of amino acid or glucose deprivation.[10][17] How the KICSTOR complex directly inhibits mTORC1 as well as senses amino acid or glucose deprivation remains to be elucidated.

Clinical Significance

Loss of the genomic locus 12q14 which contains the human protein encoding gene C12orf66 is linked to a number of developmental delays and neurodevelopment disorders such as macrocephaly.[18][19][20][21] Additionally, one study found the level of C12orf66 expression is down-regulated in colorectal cancer. In this study, the amount of C12orf66 down-regulation along with the expression of a number of other genes were used as an accurate indicator of clinical outcome in patients with colorectal cancer.[4] Thus, the level of C12orf66 gene expression reflected the survivability of these patients.[4]

Protein-Protein Interactions

C12orf66 interacts with the three proteins of the KICSTOR complex coded by the genes KPTN, ITFG2, and SZT2 as well as GATOR1.[10] Additionally, C12orf66 is predicted to interact with KRAS, DEPDC5, and C7orf60. These interactions were detected by high throughput affinity capture chromatography.[22][23]

Homologs

C12orf66 is a highly conserved protein with a large number of orthologs and no known paralogs. The list of C12orf66 orthologs includes mammals, birds, reptiles, amphibians, fish, marine worms, mollusks, insects, and fungi.[24][25]

C12orf66 Protein Orthologs
Genus and Species Common Name Time since last common ancestor (Million Years Ago)[26] Accession # (Protein)[24][27] Sequence Length Sequence Identity (ALIGN)[12] Sequence Similarity (EMBOSS Needle)[28]
Homo sapiens Human 0 mya NP_001287869.1 468 aa 100% 100%
Mus musclus House Mouse 88 mya NP_766610.2 445 aa 94.5% 91.7%
Gallus gallus Chicken 320 mya XP_416063.1 446 aa 93.3% 92.3%
Thamnophis sirtalis Garder Snake 320 mya XP_013927488.1 446 aa 89.8% 90.8%
Xenopus laevis African Clawed Frog 353 mya XP_018111484.1 478 aa 84.3% 80.9%
Danio rerio Zebrafish 432 mya NP_001025261.3 449 aa 77.5% 83.2%
Nematostella vectensis Starlett sea anemone 685 mya XP_001634917.1 440 aa 46.8% 63.9%
Branchiostoma belcheri Lancelet 699 mya XP_019643671.1 450 aa 48.9% 66.7%
Stegodyphus mimosarum Spider 758 mya KFM75667.1 492 aa 40.7% 52.2%
Lingula anatina Lingula 758 mya XP_013389803.1 438 aa 45.5% 62.0%
Saccoglossus kowalevskii Acorn worm 758 mya XP_006818351.1 421 aa 45.9% 60.8%
Priapulus caudatus Marine worm 758 mya XP_014664498.1 442 aa 43.6% 59.2%
Crassostrea gigas Pacific Oyster 758 mya XP_011430560.1 451 aa 42.2% 59.2%
Octopus bimaculoides California two-spot octopus 758 mya XP_014782952.1 504aa 37.6% 47.6%
Daphnia magna Daphnia 758 mya JAN84465.1 430 aa 39.1% 56.7%
Apis dorsata Giant Honey Bee 758 mya XP_006624940.1 428 aa 34.9% 54.0%
Polistes dominula European paper wasp 758 mya XP_015181516.1 434 aa 33.5% 53.1%
Bemisia tabaci Silverleaf whitefly 758 mya XP_018895945.1 418 aa 34.6% 52.1%
Tribolium castaneum Red Flour Beetle 758 mya KYB27801.1 551 aa 34.3% 40.8%
Lichtheimia corymbifera Lichtheimia 1150 CDH55915.1 450 aa 23.4% 38.5%

References

  1. ↑ 1.0 1.1 1.2 1.3 "C12orf66 chromosome 12 open reading frame 66 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/144577. 
  2. ↑ 2.0 2.1 2.2 "GDS3834 / 10819". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3834:10819. 
  3. ↑ Group, Schuler. "EST Profile - Hs.505871". https://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Hs.505871. 
  4. ↑ 4.0 4.1 4.2 Abdul Aziz, Nurul Ainin; Mokhtar, Norfilza M.; Harun, Roslan; Mollah, Md Manir Hossain; Mohamed Rose, Isa; Sagap, Ismail; Mohd Tamil, Azmi; Wan Ngah, Wan Zurinah et al. (2016-01-01). "A 19-Gene expression signature as a predictor of survival in colorectal cancer". BMC Medical Genomics 9 (1): 58. doi:10.1186/s12920-016-0218-1. ISSN 1755-8794. PMID 27609023. 
  5. ↑ "GDS5408 / 1554068_s_at". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS5408:1554068_s_at. 
  6. ↑ "GDS3256 / 1554067_at". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3256:1554067_at. 
  7. ↑ "GDS4557 / 235026_at". https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS4557:235026_at. 
  8. ↑ Kelley, Lawrence. "PHYRE2 Protein Fold Recognition Server". http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index. 
  9. ↑ 9.0 9.1 Database, GeneCards Human Gene. "C12orf66 Gene - GeneCards | CL066 Protein | CL066 Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=C12orf66. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Wolfson, Rachel L.; Chantranupong, Lynne; Wyant, Gregory A.; Gu, Xin; Orozco, Jose M.; Shen, Kuang; Condon, Kendall J.; Petri, Sabrina et al. (2017-02-15). "KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1". Nature 543 (7645): 438–442. doi:10.1038/nature21423. ISSN 1476-4687. PMID 28199306. Bibcode: 2017Natur.543..438W. 
  11. ↑ EMBL-EBI. "EMBL European Bioinformatics Institute" (in en). http://www.ebi.ac.uk/. 
  12. ↑ 12.0 12.1 12.2 "SDSC Biology Workbench". http://seqtool.sdsc.edu/CGI/BW.cgi. 
  13. ↑ "PSORT II Prediction". https://psort.hgc.jp/form2.html. 
  14. ↑ "SOSUI/submit a protein sequence". http://harrier.nagahama-i-bio.ac.jp/sosui/sosui_submit.html. 
  15. ↑ 15.0 15.1 "Motif Scan" (in en). http://myhits.isb-sib.ch/cgi-bin/motif_scan. 
  16. ↑ "NetPhos 3.1 Server" (in en). http://www.cbs.dtu.dk/services/NetPhos/. 
  17. ↑ 17.0 17.1 Wullschleger, Stephan; Loewith, Robbie; Hall, Michael N. (2006-02-10). "TOR signaling in growth and metabolism". Cell 124 (3): 471–484. doi:10.1016/j.cell.2006.01.016. ISSN 0092-8674. PMID 16469695. http://archive-ouverte.unige.ch/unige:18229. 
  18. ↑ Mc Cormack, Adrian; Sharpe, Cynthia; Gregersen, Nerine; Smith, Warwick; Hayes, Ian; George, Alice M.; Love, Donald R. (2015-01-01). "12q14 Microdeletions: Additional Case Series with Confirmation of a Macrocephaly Region". Case Reports in Genetics 2015. doi:10.1155/2015/192071. ISSN 2090-6544. PMID 26266063. 
  19. ↑ Lynch, Sally Ann; Foulds, Nicola; Thuresson, Ann-Charlotte; Collins, Amanda L; Annerén, Göran; Hedberg, Bernt-Oves; Delaney, Carol A; Iremonger, James et al. (2017-05-02). "The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth". European Journal of Human Genetics 19 (5): 534–539. doi:10.1038/ejhg.2010.215. ISSN 1018-4813. PMID 21267005. 
  20. ↑ Fokstuen, Siv; Kotzot, Dieter (2014-06-01). "Chromosomal rearrangements in patients with clinical features of Silver-Russell syndrome". American Journal of Medical Genetics. Part A 164A (6): 1595–1605. doi:10.1002/ajmg.a.36464. ISSN 1552-4833. PMID 24664587. 
  21. ↑ Mari, Francesca; Hermanns, Pia; Giovannucci-Uzielli, Maria L.; Galluzzi, Fiorella; Scott, Daryl; Lee, Brendan; Renieri, Alessandra; Unger, Sheila et al. (2009-09-01). "Refinement of the 12q14 microdeletion syndrome: primordial dwarfism and developmental delay with or without osteopoikilosis". European Journal of Human Genetics 17 (9): 1141–1147. doi:10.1038/ejhg.2009.27. ISSN 1476-5438. PMID 19277063. 
  22. ↑ Huttlin, Edward L.; Ting, Lily; Bruckner, Raphael J.; Gebreab, Fana; Gygi, Melanie P.; Szpyt, John; Tam, Stanley; Zarraga, Gabriela et al. (2015-07-16). "The BioPlex Network: A Systematic Exploration of the Human Interactome". Cell 162 (2): 425–440. doi:10.1016/j.cell.2015.06.043. ISSN 1097-4172. PMID 26186194. 
  23. ↑ Lab, Mike Tyers. "C12orf66 Result Summary | BioGRID" (in en). https://thebiogrid.org/126862/summary/homo-sapiens/c12orf66.html. 
  24. ↑ 24.0 24.1 "Protein BLAST: search protein databases using a protein query" (in en). https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE=Proteins. 
  25. ↑ "Human BLAT Search". https://genome.ucsc.edu/cgi-bin/hgBlat?command=start. 
  26. ↑ "TimeTree :: The Timescale of Life". http://www.timetree.org/. 
  27. ↑ "Home - Gene - NCBI". https://www.ncbi.nlm.nih.gov/gene. 
  28. ↑ EMBL-EBI. "EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI" (in en). http://www.ebi.ac.uk/Tools/psa/emboss_needle/. 



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