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CCDC188

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CCDC188
Identifiers
AliasesCCDC188, coiled-coil domain containing 188
External IDsHomoloGene: 90442; GeneCards: CCDC188; OMA:CCDC188 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

388849

102638083

Ensembl

ENSG00000234409

ENSMUSG00000090777

UniProt

H7C350

n/a

RefSeq (mRNA)

NM_001243537
NM_001365892

RefSeq (protein)

NP_001230466
NP_001352821

n/a

Location (UCSC)Chr 22: 20.15 – 20.15 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

CCDC188 or coiled-coil domain containing protein is a protein that in humans is encoded by the CCDC188 gene.[4]

Gene

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Human CCDC188 gene spans 3715 nucleotides and is located on the minus strand of chromosome 22 at 22q11.21.[5] It is a protein coding gene that encodes CCDC188 protein.[6] The mRNA transcript consists of 9 different exons which are spliced to form the 6 distinct CCDC188 protein isoforms.[7] Genetic neighbors of CCDC188 include ZDHHC8, SNORA77B, and RANBP1.

Isoform Table
Transcript Name Accession Number Exons Nucleotide length Final Protein Length (aa)
CCDC188 NM_001365892.2 9 1476 402
CCDC188 Isoform X1 XM_005261238.3 7 2501 435
CCDC188 Isoform X2 XM_005261239.3 7 2445 416
CCDC188 Isoform X4 XM_011530170.2 9 2364 402
CCDC188 Isoform X5 XM_011530171.2 7 2396 400
CCDC188 Isoform X6 XM_005261241.3 7 2393 399

RNA expression

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CCDC188 is expressed at low levels across all adult tissues with increased expression in the pituitary gland and testis.[8] CCDC188 has decreased expression in G1 of the cell cycle.

Expression in Cell Cycle

Genes with similar mRNA expression in the hypothalamus, supraoptic nucleus, and dentate gyrus are shown in the table below.

Heatmap of CCDC188 RNA Expression in Human Brain
Co-expressed Genes
Structure Gene Expande Name Function Pearson Coefficient
Hypothalamus SKAP1 Src Kinase Associated Phosphoprotein 1 Couple T-cell antigen receptor stimulation to the activation of integrins 0.71
CLIC1 Chloride Intracellular Channel 1 Nuclear chloride ion channel activity 0.659
PPAPDC1B Phospholipid Phosphatase 5 Converts diacylglycerol pyrophosphate into phosphatidate 0.656
FAM27A NA lncRNA 0.653
ZCWPW2 Zinc Finger CW-Type and PWWP Domain Containing 2 Transcription factor that binds to histone methyl groups -0.612
ZNF519 Zinc Finger Protein 519 Transcription Factor -0.61
SLC8A1 Solute Carrier Family 8 Member A1 Calcium and sodium ion exchange mediator -0.601
Supraoptic Nucleus ZNF181 Zinc Finger Protein 181 Transcription Factor 0.996
DYNC1LI1 Dynein Cytoplasmic 1 Light Intermediate Chain Intracellular trafficking and chromosome segregation during mitosis 0.991
COX18 Cytochrome C Oxidase Assembly Factor 18 Integral membrane insertion into inner mitochondrial membrane 0.991
LAMA2 Laminin Subunit Alpha 2 Attachment to basement membrane 0.991
KCTD8 Potassium Channel Tetramerization Domain Containing 8 Determines kinetics of GABA-B receptor -0.985
KLHL2 Kelch Like Family Member 2 Mediates ubiquitination of target proteins -0.985
Dentate Gyrus CXCL9 CXC Motif Chemokine Ligand 9 Antimicrobial protein 0.879
KYNU Kynureninase Biosynthesis of NAD cofactors from tryptophan 0.866
MASP1 Mannose-Binding Lectin Associated Serine Protease 1 Serine protease essential for adaptive immune response 0.808
TRPC6 Transient Receptor Potential Cation Channel Receptor activated calcium channel 0.805

The promoter region for CCDC188 contains highly conserved p53[9] and CREB-ATF4[10] binding sites.[11] Chromatin-immunoprecipitation analysis confirms p53 binding to the promoter region of CCDC188.[12] Significantly repressed CCDC188 mRNA expression is found in both testicular germ line tumors and lung squamous cell cancer.[13]

TGCT
LUSC
RNA-sequencing of CCDC188 in LUSC and TGCT (red) versus healthy samples (blue)

Copy number variations of CCDC188 have also been identified in lung squamous cell tumors with 16 tumors having amplifications and 4 having homodeletions.[14] Genes with significantly increased mRNA expression under CCDC188 amplification in lung squamous cell tumors are shown in the table below.

Upregulated Genes with CCDC188 Amplification
Gene p-Value q-Value Genetic Locus
MAGED1 3.23E-06 0.013 Xp11.22
MAPK13 5.37E-06 0.0149 6p21.31
RBM4 9.36E-06 0.0202 11q13.2
NYNRIN 3.04E-05 0.0328 14q12
HDAC7 7.1E-05 0.0486 12q13.11
ZNF675 7.25E-05 0.0486 19p12

Other predicted transcription factor binding sites for CCDC188 are shown in the figure to the right.[15]

Transcription Factor Binding Sites

Transcript regulation

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Predicted CCDC188 3'UTR stem loops are shown in the figure below.[16]

CCDC188 3'UTR

Protein

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CCDC188 Homodimer Structure

CCDC188 protein is 402 amino acids long and is 4.3 kDa.[17] The protein contains a leucine zipper and transmembrane domain.[18] The presence of both a leucine zipper domain and transmembrane domain suggests that CCDC188 protein functions as a transcription factor that is tightly regulated and must be cleaved out of a membrane to be activated. The inactive form of the protein is predicted to be located in the endoplasmic reticulum with the N-terminus and basic leucine zipper oriented in the cytosol.[19] Other membrane bound basic leucine zippers include ATF6 and OASIS.[20] Known nuclear transportation routes for membrane bound transcription factors in the endoplasmic reticulum include ubiquitination and destruction of the ER lumen region and COPII vesicular transport to the Golgi for proteolytic cleavage by resident proteases.[21]

Post-translational modifications

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Two phosphate groups have been experimentally verified on serine residues 322 and 324 in B-cell leukemia.[22]

Homology

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CCDC188 is conserved throughout all mammals including monotremes, marsupials, and placentals[23]

Ortholog Table
Clade Genus & Species Common Name Taxonomic Group Divergence Date (MYA) Accession Number Query Cover Sequence Length (aa) Sequence Identity (%) Sequence Similarity (%)
Placentals Homo sapiens Human Primate 0 NP_001352821.1 100 402 100 100
Gorilla gorilla Western Gorilla Primate 9 XP_004063092.3 100 402 97 98
Rhinopithecus roxellana Golden Snub Nosed Monkey Primate 29 XP_010386733.2 100 393 90 91
Marmota flaviventris Yellow-Bellied Marmot Rodentia 89 XP_027780043.1 100 407 76 82
Leptonychotes weddelli Weddell Seal Carnivora 94 XP_030873069.1 100 407 76 82
Ailuropoda melanoleuca Giant Panda Carnivora 94 XP_011225007.2 100 407 76 82
Canis lupus Grey Wolf Carnivora 94 XP_025330588.1 100 407 76 82
Talpa occidentalis Spanish Mole Insectivora 94 XP_037351914.1 100 406 74 79
Globicephala melas Long Finned Pilot Whale Delphinidae 94 XP_030692560.1 100 408 74 80
Molossus molossus Velvety Free-Tailed Bat Chiroptera 94 XP_036132060.1 100 404 74 79
Eptesicus fuscus Big Brown Bat Chiroptera 94 XP_008140813.2 101 404 73 80
Rhinolophus ferrumequinum Greater Horshoe Bat Chiroptera 94 XP_032953151.1 100 407 72 79
Marsupials Phascolarctos cinereus Koala Phascolarctidae 160 XP_020852118.1 41 231 44 65
Dromiciops gliroides Colocolo Opossum Microbiotheridae 160 XP_043845525.1 62 365 42 61
Monodelphis domestica Gray Short Tailed Opossum Didelphidae 160 XP_007490407.1 62 311 41 61
Vombatus ursinus Common Wombat Vombatidae 160 XP_027703176.1 62 309 40 61
Trichosurus vulpecula Brushtail Possum Phalangeroidae 160 XP_036604697.1 62 289 40 59
Sarcophilus harrisii Tasmanian Devil Dasyuridae 160 XP_031804879.1 65 313 38 52
Monotremes Ornithorhynchus anatinus Duck-Billed Platypus Platypus 180 XP_028905014.1 40 246 35 57
Tachyglossus aculeatus Short-Beaked Echidna Echidna 180 XP_038618232.1 40 383 35 55

When CCDC188 first appeared approximately 180 million years ago in monotremes, it lacked a basic leucine zipper. Marsupials were the first mammals to evolve a CCDC188 basic leucine zipper domain. The rate of evolution of CCDC188 measured by sequence identity to humans shows that CCDC188 initially evolved quickly at a rate of 0.97 changes per 100 amino acids per million years. Beginning with the first placentals, CCDC188 evolution slowed to a rate of 0.45 changes per 100 amino acids per million years. One paralog for CCDC188 exists in humans known as CCDC188-like. This gene first appeared in marsupials.

CCDC188 Rate of Evolution

Pathology

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A nonsense mutation in the coding region of CCDC188 has been implicated in retinitis pigmentosa,[24] a retinal degeneration process marked by uncontrolled death of rod cells. CCDC188 is also deleted in 22q11.2 deletion syndrome.

Diagram of CCDC188 and Nonsense Mutation Seen in Retinitis Pigmentosa

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000234409 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "coiled-coil domain-containing protein 188 [Homo sapiens]". NCBI Protein. Retrieved 2021-09-26.
  5. ^ "CCDC188 Gene". GeneCards. Retrieved 26 September 2021.
  6. ^ "CCDC188". NCBI Gene. Retrieved 28 September 2021.
  7. ^ "CCDC188". NCBI Gene. Retrieved 28 September 2021.
  8. ^ Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. (January 2015). "Proteomics. Tissue-based map of the human proteome". Science. 347 (6220): 1260419. doi:10.1126/science.1260419. PMID 25613900. S2CID 802377.
  9. ^ Fridman JS, Lowe SW (December 2003). "Control of apoptosis by p53". Oncogene. 22 (56): 9030–9040. doi:10.1038/sj.onc.1207116. PMID 14663481. S2CID 16321935.
  10. ^ Wortel IM, van der Meer LT, Kilberg MS, van Leeuwen FN (November 2017). "Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells". Trends in Endocrinology and Metabolism. 28 (11): 794–806. doi:10.1016/j.tem.2017.07.003. PMC 5951684. PMID 28797581.
  11. ^ "El Dorado". Genomatix. Intrexon Bioinformatics Germany GmbH 2019. Archived from the original on 14 January 2012. Retrieved 6 December 2021.
  12. ^ Oki S, Ohta T, Shioi G, Hatanaka H, Ogasawara O, Okuda Y, et al. (December 2018). "ChIP-Atlas: a data-mining suite powered by full integration of public ChIP-seq data". EMBO Reports. 19 (12). doi:10.15252/embr.201846255. PMC 6280645. PMID 30413482.
  13. ^ Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (July 2017). "GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses". Nucleic Acids Research. 45 (W1): W98–W102. doi:10.1093/nar/gkx247. PMC 5570223. PMID 28407145.
  14. ^ Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. (May 2012). "The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data". Cancer Discovery. 2 (5): 401–404. doi:10.1158/2159-8290.CD-12-0095. PMC 3956037. PMID 22588877.
  15. ^ "El Dorado". Genomatix. Intrexon Bioinformatics Germany GmbH 2019. Archived from the original on 14 January 2012. Retrieved 6 December 2021.
  16. ^ Markham NR, Zuker M (2008). "UNAFold". Bioinformatics. Methods in Molecular Biology. Vol. 453. pp. 3–31. doi:10.1007/978-1-60327-429-6_1. ISBN 978-1-60327-428-9. PMID 18712296.
  17. ^ "coiled-coil domain-containing protein 188 [Homo sapiens]". NCBI Protein. Retrieved 2021-09-26.
  18. ^ "coiled-coil domain-containing protein 188 [Homo sapiens]". NCBI Protein. Retrieved 2021-09-26.
  19. ^ Almagro Armenteros JJ, Sønderby CK, Sønderby SK, Nielsen H, Winther O (November 2017). "DeepLoc: prediction of protein subcellular localization using deep learning". Bioinformatics. 33 (21): 3387–3395. doi:10.1093/bioinformatics/btx431. PMID 29036616.
  20. ^ Stirling J, O'hare P (January 2006). "CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P". Molecular Biology of the Cell. 17 (1): 413–426. doi:10.1091/mbc.e05-06-0500. PMC 1345678. PMID 16236796.
  21. ^ Liu Y, Li P, Fan L, Wu M (April 2018). "The nuclear transportation routes of membrane-bound transcription factors". Cell Communication and Signaling. 16 (1): 12. doi:10.1186/s12964-018-0224-3. PMC 5883603. PMID 29615051.
  22. ^ Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E (January 2015). "PhosphoSitePlus, 2014: mutations, PTMs and recalibrations". Nucleic Acids Research. 43 (Database issue): D512–D520. doi:10.1093/nar/gku1267. PMC 4383998. PMID 25514926.
  23. ^ Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (September 1997). "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs". Nucleic Acids Research. 25 (17): 3389–3402. doi:10.1093/nar/25.17.3389. PMC 146917. PMID 9254694.
  24. ^ Yi Z, Ouyang J, Sun W, Li S, Xiao X, Zhang Q (June 2020). "Comparative exome sequencing reveals novel candidate genes for retinitis pigmentosa". eBioMedicine. 56: 102792. doi:10.1016/j.ebiom.2020.102792. PMC 7248430. PMID 32454406.
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