CCDC177

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.

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.

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.

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.