CCDC188

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

Gene

Human CCDC188 gene spans 3715 nucleotides and is located on the minus strand of chromosome 22 at 22q11.21. It is a protein coding gene that encodes CCDC188 protein. The mRNA transcript consists of 9 different exons which are spliced to form the 6 distinct CCDC188 protein isoforms. 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

CCDC188 is expressed at low levels across all adult tissues with increased expression in the pituitary gland and testis. 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.

+ 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 and CREB-ATF4 binding sites. Chromatin-immunoprecipitation analysis confirms p53 binding to the promoter region of CCDC188. Significantly repressed CCDC188 mRNA expression is found in both testicular germ line tumors and lung squamous cell cancer. Copy number variations of CCDC188 have also been identified in lung squamous cell tumors with 16 tumors having amplifications and 4 having homodeletions. 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.

Transcript regulation Predicted CCDC188 3'UTR stem loops are shown in the figure below.

Protein

CCDC188 protein is 402 amino acids long and is 4.3 kDa. The protein contains a leucine zipper and transmembrane domain. 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. Other membrane bound basic leucine zippers include ATF6 and OASIS. 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.

Post-translational modifications

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

Homology

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

+ 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.

Pathology

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

References