CCDC188 or coiled-coil domain containing protein is a protein that in humans is encoded by the CCDC188 gene. [4]
CCDC188 or coiled-coil domain containing protein is a protein that in humans is encoded by the CCDC188 gene. [4]
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.
| 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 |
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.
Genes with similar mRNA expression in the hypothalamus, supraoptic nucleus, and dentate gyrus are shown in the table below.
| 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]
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.
| 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]
Predicted CCDC188 3'UTR stem loops are shown in the figure below. [16]
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]
Two phosphate groups have been experimentally verified on serine residues 322 and 324 in B-cell leukemia. [22]
CCDC188 is conserved throughout all mammals including monotremes, marsupials, and placentals [23]
| 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.
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.
A leucine zipper is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amino acid segment and the display of these amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns. The polypeptide segments containing these periodic arrays of leucine residues were proposed to exist in an alpha-helical conformation and the leucine side chains from one alpha helix interdigitate with those from the alpha helix of a second polypeptide, facilitating dimerization.
Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs and represents between 4 and 4.5 percent of the total DNA in cells. The shorter arm is termed 11p while the longer arm is 11q. At about 21.5 genes per megabase, chromosome 11 is one of the most gene-rich, and disease-rich, chromosomes in the human genome.
CCAAT-enhancer-binding proteins is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C/EBPs can recruit so-called co-activators that in turn can open up chromatin structure or recruit basal transcription factors.
Basic Leucine Zipper and W2 Domain-Containing Protein 2 is a protein that is encoded by the BZW2 gene. It is a eukaryotic translation factor found in species up to bacteria. In animals, it is localized in the cytoplasm and expressed ubiquitously throughout the body. The heart, placenta, skeletal muscle, and hippocampus show higher expression. In various cancers, upregulation tends to lead to higher severity and mortality. It has been found to interact with SARS-CoV-2.
Transmembrane protein 8B is a protein that in humans is encoded by the TMEM8B gene. It encodes for a transmembrane protein that is 338 amino acids long, and is located on human chromosome 9. Aliases associated with this gene include C9orf127, NAG-5, and NGX61.
Iroquois-class homeodomain protein IRX-1, also known as Iroquois homeobox protein 1, is a protein that in humans is encoded by the IRX1 gene. All members of the Iroquois (IRO) family of proteins share two highly conserved features, encoding both a homeodomain and a characteristic IRO sequence motif. Members of this family are known to play numerous roles in early embryo patterning. IRX1 has also been shown to act as a tumor suppressor gene in several forms of cancer.
Nuclear factor -like factor 3, also known as NFE2L3 or 'NRF3', is a transcription factor that in humans is encoded by the Nfe2l3 gene.
Amino acid response is the mechanism triggered in mammalian cells by amino acid starvation.
The integrated stress response is a cellular stress response conserved in eukaryotic cells that downregulates protein synthesis and upregulates specific genes in response to internal or environmental stresses.
XB130 is a cytosolic adaptor protein and signal transduction mediator. XB130 regulates cell proliferation, cell survival, cell motility and gene expression. XB130 is highly similar to AFAP and is thus known as actin filament associated protein 1-like 2 (AFAP1L2). XB130 is a substrate and regulator of multiple tyrosine kinase-mediated signaling. XB130 is highly expressed in the thyroid and spleen.
Coiled Coil Domain Containing protein 42B, also known as CCDC42B, is a protein encoded by the protein-coding gene CCDC42B.
Solute carrier family 46 member 3 (SLC46A3) is a protein that in humans is encoded by the SLC46A3 gene. Also referred to as FKSG16, the protein belongs to the major facilitator superfamily (MFS) and SLC46A family. Most commonly found in the plasma membrane and endoplasmic reticulum (ER), SLC46A3 is a multi-pass membrane protein with 11 α-helical transmembrane domains. It is mainly involved in the transport of small molecules across the membrane through the substrate translocation pores featured in the MFS domain. The protein is associated with breast and prostate cancer, hepatocellular carcinoma (HCC), papilloma, glioma, obesity, and SARS-CoV. Based on the differential expression of SLC46A3 in antibody-drug conjugate (ADC)-resistant cells and certain cancer cells, current research is focused on the potential of SLC46A3 as a prognostic biomarker and therapeutic target for cancer. While protein abundance is relatively low in humans, high expression has been detected particularly in the liver, small intestine, and kidney.
Transmembrane protein 261 is a protein that in humans is encoded by the TMEM261 gene located on chromosome 9. TMEM261 is also known as C9ORF123 and DMAC1, Chromosome 9 Open Reading Frame 123 and Transmembrane Protein C9orf123 and Distal membrane-arm assembly complex protein 1.
Retrotransposon Gag Like 6 is a protein encoded by the RTL6 gene in humans. RTL6 is a member of the Mart family of genes, which are related to Sushi-like retrotransposons and were derived from fish and amphibians. The RTL6 protein is localized to the nucleus and has a predicted leucine zipper motif that is known to bind nucleic acids in similar proteins, such as LDOC1.
Chromosome 19 open reading frame 18 (c19orf18) is a protein which in humans is encoded by the c19orf18 gene. The gene is exclusive to mammals and the protein is predicted to have a transmembrane domain and a coiled coil stretch. This protein has a function that is not yet fully understood by the scientific community.
Transmembrane protein 171 (TMEM171) is a protein that in humans is encoded by the TMEM171 gene.
WD Repeat and Coiled-coiled containing protein (WDCP) is a protein which in humans is encoded by the WDCP gene. The function of the protein is not completely understood, but WDCP has been identified in a fusion protein with anaplastic lymphoma kinase found in colorectal cancer. WDCP has also been identified in the MRN complex, which processes double-stranded breaks in DNA.
Transmembrane protein 211 (TMEM211,bA9F11.1,Q6ICI0,LHFLP7) is a tetraspan membrane protein under the LHFPL subfamily. It primarily plays a role in the perception of sound but may have secondary roles in insulin signaling. It is encoded by the TMEM211 gene and is found in almost all animals.
Transmembrane epididymal protein 1 is a transmembrane protein encoded by the TEDDM1 gene. TEDDM1 is also commonly known as TMEM45C and encodes 273 amino acids that contains six alpha-helix transmembrane regions. The protein contains a 118 amino acid length family of unknown function. While the exact function of TEDDM1 is not understood, it is predicted to be an integral component of the plasma membrane.
