Coiled-Coil Domain Containing 177 (CCDC177) is a protein, which in humans, is encoded by the gene CCDC177. It is composed of a coiled helical domain that spans half of the protein. CCDC177 deletions are associated with intellectual disability and congenital heart defects.
Gene
The CCDC177 gene is located on chromosome 14 at 14q24.1, and contains 2 exons.
The CCDC177 gene is part of the CCDC gene family, which encodes proteins involved in signal transduction and signal transcription.
Other known aliases for the CCDC177 gene are Chromosome 14 Open Reading Frame 162 (C14orf162), and Myelin Proteolipid Protein-Like Protein (PLPL).
mRNA transcripts CCDC177 has one variant, which encodes Isoform 1 in humans. The mRNA sequence for this variant is 4,182 base pairs in length. Both exons are present in the variant, however the coding region is entirely within Exon 2.
Protein
CCDC177 Isoform 1 in humans is 707 amino acids long with a predicted molecular weight of 80 kDa. It is rich in arginine, and glutamate, and poor in isoleucine relative to other proteins. The isoelectric point is 11. The human protein is also rich in arginine-glutamate motifs, which are implicated in cell survival signaling.
Domains and motifs Humans CCDC177 includes one domain of unknown function (DUF4659), multiple disordered regions, and an alanine-rich motif.
Structure Proteins of the coiled coil domain containing (CCDC) family contain large coiled helical domains. The coiled helical domain within the human CCDC177 protein fully overlaps the domain of unknown function (DUF4659).
Gene-level regulation CCDC177 mRNA is ubiquitously expressed across adult human tissues, but is low in expression in fetal tissues throughout the body. It is also less abundant in immune cells such as B cells, T cells, and NK cells.
Protein-level regulation
Sub-cellular location Human CCDC177 contains multiple nuclear localization signals, indicating that is found in the nucleus. The protein also contains multiple nuclear export signals, indicating protein movement between the nucleus and cytosol. The locations of the various kinases phosphorylating the CCDC177 protein implicate phosphorylation in CCDC177's movement between the nucleus and cytosol.Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015 43:D512-20.
Post translational modifications In CCDC177, phosphorylation and O-GlcNAc modifications are predicted to occur on several serine residues, while SUMOylation occurs on select lysine residues.
The types of kinases that phosphorylate highly conserved serine residues (conserved across current CCDC177 orthologs) in the CCDC177 protein sequence are located in the nucleus and cytosol. These kinases include Protein Kinase A which is located in the cytosol and nucleus, Cyclin-dependent kinase 5 located in the cytosol, and Protein Kinase C located in the nucleus.
Conservation CCDC177 has no paralogs in humans. Orthologs are currently found in mammals, birds, reptiles, amphibians, fish, and invertebrates.
+ Current CCDC177 Orthologs Organism ("Genus Species") Common name Taxonomic Order Median Date of Divergence (MYA) Accession # Sequence length (aa) Sequence identity to human protein (%) ! !Sequence similarity to Human Protein (%) Homo sapiens Human Hominidae 0 NP_001258436.1 707 100 100 Mus musculus Mouse Rodentia 87 NP_001008423.2 706 90.6 94.1 Equus caballus Horse Perissodactyla 94 XP_023483759.1 700 93.9 95.3 Suncus etruscus Etruscan Shrew Eulipotyphla 94 XP_049626320.1 712 78.9 85.2 Phascolarctos cinereus Koala Marsupialia 160 XP_020860505.1 709 73 82 Ornithorhynchus anatinus Platypus Monotremata 180 XP_028920460.1 700 67.6 75.9 Gallu gallus Chicken Galliformes 319 XP_040527977.1 692 54.8 67.5 Aix galericulata Mandarin Duck Anseriformes 319 KAI6068518.1 709 49.7 62.8 Sceloporus undulatus Eastern Fence Lizard Iguania 319 XP_042299999.1 710 52.9 68.8 Gopherus flavomarginatus Bolson Tortoise Testudines 319 XP_050809463.1 714 51.7 65.3 Python bivittatus Burmese Python Serpentes 319 XP_007441661.1 740 49.0 62.8 Geotrypetes seraphini Gaboon Caecilian Gymnophiona 352 XP_033808243.1 663 47.6 63.2 Spea bombifrons Plains Spadefoot Toad Anura 352 XP_053330589.1 688 41.1 58.9 Xenopus tropicalis Western Clawed Frog Anura 352 XP_002935376.2 679 40.6 58.6 Lepisosteus oculatus Spotted Gar Lepisosteiformes 429 XP_015206663.1 712 46.5 61.9 Silurus meridionalis Large-mouth Catfish Siluriformes 429 KAI5102643.1 707 45.2 60.8 Callorhinchus milii Australian Ghostshark Chimaeriformes 462 XP_042189074.1 710 27.8 43.6 Styela clava Stalked Sea Squirt Stolidobranchia 596 XP_039248961.1 678 21.7 38.9 Actinia tenebrosa Waratah Anemone Actiniaria 715 XP_031562596.1 712 28.0 44.4 Orbicella faveolata Mountainous Star Coral Scleractinia 715 XP_020615800.1 718 25.2 40.9
Rate of evolution The protein encoded by CCDC177 evolves twice as fast as Cytochrome c and slightly slower than fibrinogen alpha, indicating that the CCDC177 gene has a moderately fast rate of evolution.
Interacting proteins Human CCDC177 protein has notable interactions with the following proteins which are all associated with development and stem cell differentiation. All of the following proteins are located in the nucleus. These interactions implicate human CCDC177 in developmental processes and cell survival, and support its location in the nucleus.
MYC binding protein 2 (MYCBP2) regulates neuronal growth and is required for proper axon growth. Forkhead box protein N4 (FOXN4) is a transcription factor required for neural development and growth. It is especially important for specifying the fates of multipotent retinal progenitors. Histone Deacetylase 5 (HDAC5) deacetylates lysine residues on the N-terminus tail of core histones and promotes cell cycle progression. T-cell acute lymphocytic leukemia protein 1 (TAL1) is an oncogenic transcription factor in T-cell acute lymphoblastic leukemia, and is implicated in hematopoietic stem cell differentiation.
Clinical significance The CCDC177 gene can be utilized to develop prognostic tumor markers for neuroblastomas, thyroid cancer, and lung cancer. CCDC177 is a methylation-driven gene in thyroid cancer, which was determined by examining proliferation and invasion of thyroid cancer (TC) cells in CCDC177 knockdown vectors. TC cells containing knockdown CCDC177 were highly proliferative and invasive.
Prognostic tumor methylation markers were discovered in human neuroblastoma as well. 78 significantly differentially methylated regions were identified from 396 sequenced tumor profiles. Methylation-specific PCR assays were also developed to determine which regions accurately predict survival outcomes. 5 of the 78 assays, including one located in CCDC177, predicted event-free survival. CCDC177 mRNA is also integral to the accurate prediction of overall survival in lung squamous cell carcinoma (LUSC) patients.
Interstitial deletions of chromosome 14 at the location 14q24.1q24.3, which includes CCDC177, are linked to mild intellectual disability, congenital heart defects, and brachydactyly. Haploinsufficiency in one or several of the deleted genes is the cause for the deletions.
References