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Coiled-Coil Domain Containing 177 (CCDC177) is a protein, which in humans, is encoded by the gene CCDC177.[1] 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.[2]

Gene[edit]

The CCDC177 Gene is located on chromosome 14 at 14q24.1, and contains 2 exons.

The location of the CCDC177 gene on chromosome 14 at 14q24.1.[1]

The CCDC177 gene is part of the CCDC gene family, which encodes proteins involved in signal transduction and signal transcription.[3]

Other known aliases for the CCDC177 gene are Chromosome 14 Open Reading Frame 162 (C14orf162), and Myelin Proteolipid Protein-Like Protein (PLPL).[1]

mRNA Transcripts[edit]

CCDC177 has 1 variant, which encodes Isoform 1 in humans. The mRNA sequence for this variant is 4,182 base pairs in length.[1] Both exons are present in the variant, however the coding region is entirely within Exon 2.

Protein[edit]

The predicted tertiary structure of human CCDC177 protein from AlphaFold.[4]

CCDC177 Isoform 1 in humans is 707 amino acids long[1] with a predicted molecular weight of 80 kDa.[5] It is rich in arginine, and glutamate, and poor in isoleucine relative to other proteins. The isoelectric point is 11.[6] The human protein is also rich in arginine-glutamate motifs, which are implicated in cell survival signaling.[7]

Domains & Motifs[edit]

Humans CCDC177 includes one domain of unknown function (DUF4659), multiple disordered regions, and an alanine-rich motif.[1]

Structure[edit]

Proteins of the coiled coil domain containing (CCDC) family contain large coiled helical domains.[8][9] The coiled helical domain within the human CCDC177 protein fully overlaps the domain of unknown function (DUF4659).

Large-scale Analysis of the Human Transcriptome [Profile GDS596] from NCBI GeoProfiles.[10]

Gene-Level Regulation[edit]

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.[10]

Protein-Level Regulation[edit]

Sub-cellular Location[edit]

Human CCDC177 contains multiple nuclear localization signals, indicating that is is found in the nucleus.[11] The protein also contains multiple nuclear export signals, indicating protein movement between the nucleus and cytosol.[12] The locations of the various kinases phosphorylating the CCDC177 protein implicate phosphorylation in CCDC177’s movement between the nucleus and cytosol.[13]

Post Translational Modifications[edit]

CCDC177 post-translational modifications and other notable motifs. Created using IBS-Data Visualization[14]

In CCDC177, phosphorylation and O-GlcNAc modifications are predicted to occur on several serine residues,[15] while SUMOylation occurs on select lysine residues.[16]

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,[17] Cyclin-dependent kinase 5 located in the cytosol,[18] and Protein Kinase C located in the nucleus.[19]

Human CCDC177 Conceptual Translation annotated with specific motifs of interest, signal sequences, post-translational modifications and other predicted domains. Labels for each annotation are found in the margins of the conceptual translation.

Conservation[edit]

CCDC177 has no paralogs in humans. Orthologs are currently found in mammals, birds, reptiles, amphibians, fish, and invertebrates.[20]

Current CCDC177 Orthologs[21]
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 (%)
Mammals 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
Birds 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
Reptiles 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
Amphibians 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
Fish 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
Invertebrates 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[edit]

The following graph shows the rate of evolution of CCDC177 compared to that of Cytochrome C and Fibrinogen Alpha.

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[edit]

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.[22]
  • 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.[23]
  • Histone Deacetylase 5 (HDAC5) deacetylates lysine residues on the N-terminus tail of core histones and promotes cell cycle progression.[24]
  • 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.[25]
Circles indicate similar species. Made using Phylogeny.fr[26]

Clinical Significance[edit]

The CCDC177 gene can be utilized to develop prognostic tumor markers for neuroblastomas,[27] thyroid cancer,[28] and lung cancer.[29] 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.[30] 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.[31]Haploinsufficiency in one or several of the deleted genes is the cause for the deletions.

References[edit]

  1. ^ a b c d e f "CCDC177 coiled-coil domain containing 177 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-12-16.
  2. ^ Oehl‐Jaschkowitz, Barbara; Vanakker, Olivier M.; De Paepe, Anne; Menten, Björn; Martin, Thomas; Weber, Georg; Christmann, Alexander; Krier, Romain; Scheid, Simone; McNerlan, Susan E.; McKee, Shane; Tzschach, Andreas. "Deletions in 14q24.1q24.3 are associated with congenital heart defects, brachydactyly, and mild intellectual disability". American Journal of Medical Genetics Part A. 164 (3): 620–626. doi:10.1002/ajmg.a.36321. ISSN 1552-4825.
  3. ^ Liu, Zhen; Yan, Weiwei; Liu, Shaohua; Liu, Zhan; Xu, Ping; Fang, Weiyi (2023-07-01). "Regulatory network and targeted interventions for CCDC family in tumor pathogenesis". Cancer Letters. 565: 216225. doi:10.1016/j.canlet.2023.216225. ISSN 0304-3835.
  4. ^ "AlphaFold Protein Structure Database". alphafold.ebi.ac.uk. Retrieved 2023-12-16.
  5. ^ "SAPS < Sequence Statistics < EMBL-EBI". www.ebi.ac.uk. Retrieved 2023-12-16.
  6. ^ Kozlowski, Lukasz P. "IPC - ISOELECTRIC POINT CALCULATION OF PROTEINS AND PEPTIDES". isoelectric.org. Retrieved 2023-12-16.
  7. ^ Chandana, Thimmegowda; P. Venkatesh, Yeldur (2016-05-25). "Occurrence, Functions and Biological Significance of Arginine-Rich Proteins". Current Protein & Peptide Science. 17 (5): 507–516. doi:10.2174/1389203717666151201192348.
  8. ^ Liu, Zhen; Yan, Weiwei; Liu, Shaohua; Liu, Zhan; Xu, Ping; Fang, Weiyi (2023-07-01). "Regulatory network and targeted interventions for CCDC family in tumor pathogenesis". Cancer Letters. 565: 216225. doi:10.1016/j.canlet.2023.216225. ISSN 0304-3835.
  9. ^ Priyanka, Patra Priyadarshini; Yenugu, Suresh. "Coiled-Coil Domain-Containing (CCDC) Proteins: Functional Roles in General and Male Reproductive Physiology". Reproductive Sciences. 28 (10): 2725–2734. doi:10.1007/s43032-021-00595-2. ISSN 1933-7191.
  10. ^ a b "GDS596 / 220887_at". www.ncbi.nlm.nih.gov. Retrieved 2023-12-16.
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  18. ^ Ino, H.; Chiba, T. (1996-09-02). "Intracellular localization of cyclin-dependent kinase 5 (CDK5) in mouse neuron: CDK5 is located in both nucleus and cytoplasm". Brain Research. 732 (1–2): 179–185. doi:10.1016/0006-8993(96)00523-9. ISSN 0006-8993. PMID 8891282.
  19. ^ Ringvold, H. C.; Khalil, R. A. (2017-01-01), Khalil, Raouf A. (ed.), "Chapter Six - Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders", Advances in Pharmacology, Vascular Pharmacology, vol. 78, Academic Press, pp. 203–301, doi:10.1016/bs.apha.2016.06.002, PMC 5319769, PMID 28212798, retrieved 2023-12-16{{citation}}: CS1 maint: PMC format (link)
  20. ^ "Protein BLAST: search protein databases using a protein query". blast.ncbi.nlm.nih.gov. Retrieved 2023-12-16.
  21. ^ Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403-10. doi: 10.1016/S0022-2836(05)80360-2. PMID: 2231712.
  22. ^ AlAbdi, Lama; Desbois, Muriel; Rusnac, Domniţa-Valeria; Sulaiman, Raashda A; Rosenfeld, Jill A; Lalani, Seema; Murdock, David R; Burrage, Lindsay C; Undiagnosed Diseases Network; Billie Au, Ping Yee; Towner, Shelley; Wilson, William G; Wong, Lawrence; Brunet, Theresa; Strobl-Wildemann, Gertrud (2023-04-19). "Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects". Brain. 146 (4): 1373–1387. doi:10.1093/brain/awac364. ISSN 0006-8950.
  23. ^ Islam, Mohammed M.; Li, Ying; Luo, Huijun; Xiang, Mengqing; Cai, Li (2013-11-15). "Meis1 regulates Foxn4 expression during retinal progenitor cell differentiation". Biology Open. 2 (11): 1125–1136. doi:10.1242/bio.20132279. ISSN 2046-6390. PMC 3828759. PMID 24244849.{{cite journal}}: CS1 maint: PMC format (link)
  24. ^ Wang, Yaomei; Li, Wei; Schulz, Vincent P.; Zhao, Huizhi; Qu, Xiaoli; Qi, Qian; Cheng, Yong; Guo, Xinhua; Zhang, Shijie; Wei, Xin; Liu, Donghao; Yazdanbakhsh, Karina; Hillyer, Christopher D.; Mohandas, Narla; Chen, Lixiang (2021-10-28). "Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency". Blood. 138 (17): 1615–1627. doi:10.1182/blood.2020007401. ISSN 0006-4971.
  25. ^ Hoang, T.; Lambert, J.A.; Martin, R. (2016), "SCL/TAL1 in Hematopoiesis and Cellular Reprogramming", Current Topics in Developmental Biology, vol. 118, Elsevier, pp. 163–204, doi:10.1016/bs.ctdb.2016.01.004, ISBN 978-0-12-803319-7, retrieved 2023-12-16
  26. ^ "NGPhylogeny.fr". ngphylogeny.fr. Retrieved 2023-12-16.
  27. ^ Ram Kumar, Ram Mohan; Schor, Nina Felice (2018-04-24). "Methylation of DNA and chromatin as a mechanism of oncogenesis and therapeutic target in neuroblastoma". Oncotarget. 9 (31): 22184–22193. doi:10.18632/oncotarget.25084. ISSN 1949-2553. PMC 5955135. PMID 29774131.{{cite journal}}: CS1 maint: PMC format (link)
  28. ^ Chen, Zhiwei; Liu, Xiaoli; Liu, Fangfang; Zhang, Guolie; Tu, Haijian; Lin, Wei; Lin, Haifeng (2021-08-31). "Identification of 4-methylation driven genes based prognostic signature in thyroid cancer: an integrative analysis based on the methylmix algorithm". Aging. 13 (16): 20164–20178. doi:10.18632/aging.203338. ISSN 1945-4589. PMC 8436924. PMID 34456184.{{cite journal}}: CS1 maint: PMC format (link)
  29. ^ Ju, Qiang; Zhao, Yan-jie; Ma, Sai; Li, Xin-mei; Zhang, Heng; Zhang, Shao-qiang; Yang, Yuan-ming; Yan, Song-xia. "Genome-wide analysis of prognostic-related lncRNAs, miRNAs and mRNAs forming a competing endogenous RNA network in lung squamous cell carcinoma". Journal of Cancer Research and Clinical Oncology. 146 (7): 1711–1723. doi:10.1007/s00432-020-03224-8. ISSN 0171-5216.
  30. ^ for the Children’s Cancer and Leukaemia Group (CCLG); Decock, Anneleen; Ongenaert, Maté; Cannoodt, Robrecht; Verniers, Kimberly; De Wilde, Bram; Laureys, Geneviève; Van Roy, Nadine; Berbegall, Ana P.; Bienertova-Vasku, Julie; Bown, Nick; Clément, Nathalie; Combaret, Valérie; Haber, Michelle; Hoyoux, Claire. "Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma". Oncotarget. 7 (2): 1960–1972. doi:10.18632/oncotarget.6477. ISSN 1949-2553. PMC 4811509. PMID 26646589.{{cite journal}}: CS1 maint: PMC format (link)
  31. ^ Oehl‐Jaschkowitz, Barbara; Vanakker, Olivier M.; De Paepe, Anne; Menten, Björn; Martin, Thomas; Weber, Georg; Christmann, Alexander; Krier, Romain; Scheid, Simone; McNerlan, Susan E.; McKee, Shane; Tzschach, Andreas. "Deletions in 14q24.1q24.3 are associated with congenital heart defects, brachydactyly, and mild intellectual disability". American Journal of Medical Genetics Part A. 164 (3): 620–626. doi:10.1002/ajmg.a.36321. ISSN 1552-4825.
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