CCDC138

Coiled-coil domain-containing protein 138, also known as CCDC138, is a human protein encoded by the CCDC138 gene. The exact function of CCDC138 is unknown.

CCDC138
Identifiers
Aliases	CCDC138, coiled-coil domain containing 138
External IDs	MGI: 1923388; HomoloGene: 44912; GeneCards: CCDC138; OMA:CCDC138 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q13 Start 108,786,757 bp[1] End 108,885,477 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10|10 B4 Start 58,497,948 bp[2] End 58,576,244 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle sperm ventricular zone olfactory zone of nasal mucosa ganglionic eminence gonad secondary oocyte right uterine tube Achilles tendon bronchial epithelial cell Top expressed in spermatid zygote spermatocyte tail of embryo genital tubercle ventricular zone right kidney embryo morula embryo More reference expression data BioGPS n/a
Orthologs Species Human Mouse Entrez 165055 76138 Ensembl ENSG00000163006 ENSMUSG00000038010 UniProt Q96M89 Q0VF22 RefSeq (mRNA) NM_001303105 NM_001303106 NM_144978 NM_001351544 NM_001351545 NM_001351548 NM_001351549 NM_001351551 NM_001351553 NM_001351554 NM_001351555 NM_001351557 NM_001351559 NM_001351561 NM_001351565 NM_001162956 RefSeq (protein) NP_001290034 NP_001290035 NP_659415 NP_001338473 NP_001338474 NP_001338477 NP_001338478 NP_001338480 NP_001338482 NP_001338483 NP_001338484 NP_001338486 NP_001338488 NP_001338490 NP_001338494 NP_001156428 Location (UCSC) Chr 2: 108.79 – 108.89 Mb Chr 10: 58.5 – 58.58 Mb PubMed search [3] [4]
Wikidata
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Gene

The CCDC138 gene can be found at the positive strand of chromosome 2.^[5]

Locus

The CCDC138 gene is located at the long(q) arm of chromosome 2 at locus 12.13,^[6] or in short 2q12.3. It can be found at location 108,786,752-108,876,591.^[7] The DNA sequence is 89,840bp long.

The red line shows the CCDC138 locus on chromosome 2q12.3.

Common aliases

CCDC138 is the only established common alias.

Homology and evolution

Paralogs

No paralogs of CCDC138 have been identified.

Orthologs

CCDC138 is conserved in various organisms as shown in the table below.

Scientific name	Common name	Date of divergence from human lineage[8]	Sequence length	Sequence identity to human RNA/protein	Sequence similarity to human RNA/protein
Mus musculus	House mouse	92.3 MYA	2466 bp	77%	65.7%
Columbia livia	Rock dove	296 MYA	1863 bp	61%	59.4%
Xenopus laevis	African clawed frog	371.2 MYA	2634 bp	52%	40.1%
Anolis carolinensis	Red-throated anole	296 MYA	9588 bp	78%	46.3%
Latimeria chalumnae	West Indian Ocean coelacanth	414.9 MYA	1838 bp	71%	38.1%
Strongylocentrotus purpuratus	Purple sea urchin	742.9 MYA	2047 bp	59%	14.5%
Ciona intestinalis	Vase tunicate	722.5 MYA	2420 bp	56%	23.8%
Aplysia californica	California sea slug	782.7 MYA	2103 bp	49%	17.2%
Hydra vulgaris	Fresh-water polyp	855.3 MYA	1482 bp	46%	13.7%
Chrysemys picta bellii	Western painted turtle	296 MYA	700 bp	36%	15.9%
Alligator mississippiensis	American alligator	296 MYA	2089 bp	76%	38.4%
Melopsittacus undulatus	Budgerigar	296 MYA	1764 bp	73%	40.3%
Taeniopygia guttata	Zebra finch	296 MYA	1980 bp	75%	44.2%
Lepisosteus oculatus	Spotted gar	400.1 MYA	1269 bp	65%	30.9%
Saccoglossus kowalevskii	Acorn worm	661.2 MYA	2515 bp	42%	24.1%
Branchiostoma floridae	Lancelet	713.2 YA	1758 bp	55%	27.0%
Maylandia zebra	Zebra mbuna fish	400.1 MYA	4815 bp	58%	21.4%
Trichoplax adhaerens	Trichoplax	800 MYA	1605 bp	56%	10.3%
Pelodiscus sinensis	Chinese softshell turtle	296 MYA	2895 bp	77%	33.9%
Falco cherrug	Saker falcon	296 MYA	1866 bp	73%	48.9%

Distant homologs

The most distant homolog detected or predicted is Trichoplax adhaerans. It has a conserved CCDC138 gene and has evolved 800 MYA before the human lineage.

Homologous domains

Among the orthologs stated above, there are various homologous regions that are conserved shown in figures below.

CCDC138 multiple sequence alignment showing conserved regions.

CCDC138 multiple sequence alignment showing conserved regions.

CCDC138 multiple sequence alignment showing conserved regions.

Green colors shows completely conserved residues, yellow color shows identical residues, cyan color shows similar residues, white color shows different residues.

Phylogeny

The observed phylogeny of the CCDC138 gene of the above mentioned orthologs recapitulates the evolutionary history.^[9]

CCDC138 rooted phylogeny tree

The figure above shows the evolutionary relationship of CCDC138 in the orthologs.

Protein

The CCDC138 protein is predated to have a molecular weight of 76.2Kda^[10] and an isoelectric point of 8.614.^[11] Compositional analysis shows that there is a low usage of the AGP grouping in CCDC138, and there are no positive, negative or mixed charge clusters. The protein has no ER retention motif in the C-terminus and no RNA binding motif.^[12] It has also been predicted to be a soluble nuclear protein with a leucine zipper pattern (PS00029) at position 205 onwards with a sequence LQKRERFLLEREQLLFRHENAL.^[12]

Primary sequence and variants/isoforms

There are two isoforms of the CCDC138 protein. The primary isoform has 665 amino acids^[13] while the secondary isoform has 577 amino acids,^[13] and is missing 88 amino acids at the C-terminus.

Pairwise sequence alignment comparing isoforms 1 and 2 of the CCDC138 protein.

Figure shows the pairwise sequence alignment comparing the primary isoform (Isoform 1) to the secondary isoform (Isoform 2).

Domain and motifs

A domain of unknown function (DUF2317) on the protein at location 212 – 315 has been characterized in bacteria. TMHMM^[14] and TMAP^[15] suggests that there are no predicted transmembrane domain. SOSUI^[16] further predicts that CCDC138 is a soluble protein with no transmembrane domain.

Post-translational modifications

According to SUMOplot Analysis Program,^[17] there are 7 predicted sumoylation at lysine residues K7, K207, K336, K374, K383, K521, and K591. NetPhos^[18] predicts that there are 44 phosphorylations sites, including 29 serine residues, 10 threonine residues, and 5 tyrosine residues. There are no further post-translational modifications as predicted by NetNGlyc,^[19] NetOGlyc,^[20] SignalP,^[21] Sulfinator,^[22] and Myristoylator.^[23]

Secondary structure

The CCDC138 protein contains multiple alpha helixes, beta sheets and coiled-coils as predicted by PELE, CHOFAS, and GOR4.

CCDC138 secondary structure as predicted by PELE

Yellow shows coiled-coil, blue shows alpha helix, and red shows beta sheet. The majority of the sequence are coiled-coils and alpha helixes.

3° and 4° structures

There are no predicted 3° and 4° Structures for the CCDC138 protein. However, there is a similar structure that has a 29% identity.^[24] The predicted structure is Chain A, crystal structure analysis of Clpb, a protein that encodes an ATP-dependent protease and chaperone. This protein has an aligned-length of 144 amino acids, and the alignment is located at the domain of unknown function of CCDC138.

Chain A, crystal analysis structure of Clpb

Expression

The gene is expressed at low levels in almost all human tissues, but higher levels have been seen in certain cancer tissues. CCDC138 is a soluble protein that is pre diced to localise in the nucleus of a cell.

Promoter

The promoter region of CCDC138 is shown as figure below.

Promoter region of CCDC138 with labeled transcription factor binding sites

Expression

Microarray-assessed tissue expression patterns through GEO profiles show that CCDC138 is expressed in moderate levels in various tissues including peripheral blood lymphocyte, fetal thymus, thymus, testis, ovary, feral brain, colon, mammary gland, and bone marrow.^[25]

Microarray-assessed tissue expression patterns shown in GEO profile.

Transcript variants

There are two most significant alternative transcript variants for CCDC138 mRNA. The first variant as shown in the figure below has been found in lung, blood, and human embryonic stem cells.^[26] The second variant has been found in adenocarcinoma, prostate, lung, and primary lung epithelial cells.^[27]

Transcript variants of CCDC138

First transcript shows the complete mRNA transcript. Second transcript is the first variant, while the thirst transcript is the second variant.^[28]

Function and biochemistry

The exact function of CCDC138 is yet to be known.

Interacting proteins

The CCDC138 protein has been found to interact with ubiquitin C,^[29] a protein involved in ubiquination and eventually protein degradation.

Transcription factors that might bind to regulatory sequence

The table below shows some transcription factors that have been predicted by Genomatix that binds to the regulatory sequence of the CCDC138 gene.^[30]

Detailed family information	Detailed matrix information	Tissue
GC-Box factors SP1/GC	Stimulating protein 1, ubiquitous zinc finger transcription factor	Ubiquitous
Peroxisome proliferator-activated receptor	Peroxisome proliferator-activated receptor gamma, DR1 sites	Adipose Tissue, Connective Tissue, Digestive System, Liver
MYT1 C2HC zinc finger protein	MyT1 zinc finger transcription factor involved in primary neurogenesis	Central Nervous System, Nervous System, Neuroglia, Neurons
NGFI-B response elements, nur subfamily of nuclear receptors	Monomers of the nur subfamily of nuclear receptors (nur77, nurr1, nor-1)	Brain, Central Nervous System, Endocrine System, Immune System, Leydig Cells, Nervous System, Neurons, Testis, Thymus Gland, Urogenital System
Krueppel-like transcription factors	Core promoter-binding protein (CPBP) with 3 Krueppel-type zinc fingers (KLF6, ZF9)	Blood cells, bone marrow cells, digestive system, embryonic structures, Erythrocytes, Hematopoietic System, liver
Grainyhead-like transcription factors	Grainyhead-like 3 (sister-of-mammalian grainyhead - SOM)	Embryonic Structures, Integumentary System
CTCF and BORIS gene family, transcriptional regulators with 11 highly conserved zinc finger domains	Insulator protein CTCF (CCCTC-binding factor)	Blood Cells, Embryonic Structures, Endocrine System, Erythrocytes, Germ Cells, Testis, Urogenital System
Core promoter motif ten elements	Human motif ten element	-
Abdominal-B type homeodomain transcription factors	Homeobox C13 / Hox-3gamma	Bone Marrow Cells, Bone and Bones, Central Nervous System, Connective Tissue, Embryonic Structures, Hematopoietic System, Integumentary System, Kidney, Nervous System, Neurons, Prostate, Skeleton, Spinal Cord, Urogenital System
E2F-myc activator/cell cycle regulator	E2F transcription factor 2	Ubiquitous
PAX-3 binding sites	Pax-3 paired domain protein, expressed in embryogenesis, mutations correlate to Waardenburg Syndrome	Embryonic structures, muscle, skeletal, muscles
ZF5 POZ domain zinc finger	ZF5 POZ domain zinc finger, zinc finger protein 161	-
Vertebrate TATA binding protein factor	Cellular and viral TATA box elements	-
CCAAT binding factors	Avian C-type LTR CCAAT box	Ubiquitous
Ccaat/Enhancer Binding Protein	CCAAT/enhancer binding protein alpha	Adipose Tissue, Bone Marrow Cells, Connective Tissue, Digestive System, Hematopoietic System, Immune System, Liver, Myeloid Cells, Phagocytes
Activator-, mediator- and TBP-dependent core promoter element for RNA polymerase II transcription from TATA-less promoters	X gene core promoter element 1	-

Clinical significance

CCDC138 has been identified as one of the many genes involved in initiating term labor in myometrium.^[31]