Ccdc109b

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Coiled-coil domain containing 109B (CCDC109B) is a potential calcium uniporter protein found in the membrane of human cells and is encoded by the CCDC109B gene. While CCDC109B is a transmembrane protein it is unclear if it is located within the cell membrane or mitochondrial membrane.

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human

Gene information

CCDC109B is located at 4q25 and is 128,520 base pairs in length. CCDC109B contains eight exons and is located on the positive strand of chromosome four. CCDC109B has nine transcript variants due to alternative splicing.[1] The unspliced version of this gene is the longest and most common variant found in human cells and is 1298 base pairs in length.

File:CCDC109B Location.jpg
Location of CCDC109B gene on Chromosome 4.

Protein information

When translated, the CCDC109B protein is composed of 336 amino acids and has a molecular weight of 39.1 kDa. The 3' end of this protein is highly conserved and contains domains crucial for protein function.

Protein domains

  • Domain of Unknown Function 607 (DUF607): The function of this domain is largely unknown, although it may serve as a calcium transporter when CCDC109B forms homo-oligimers. DUF607 is conserved in orthologs and is located closer to the 3' end of this protein, even though DUF607 is present for most of the protein's length.[2]
File:CCDC109B Overview.jpg
Overview of the major domains present in CCDC109B.
  • Transmembrane Region: CCDC109B contains two transmembrane regions, located within DUF607, making it a multipass membrane protein. Since there are two transmembrane regions, both the N-terminus and C-terminus are located on one side of the membrane and have been localized to the cytosolic side of the cell membrane.[2]
File:CCDC109B Transmembrane.jpg
General view of CCDC109B as a transmembrane protein. The top of the image shows the cytosolic end of the protein. The bottom of the image shows the DIME Motif which is completely conserved in all organisms that have either CCDC109B or its paralog, MCU
  • DIME Motif: This motif is a completely conserved region found in all orthologs of this protein and is found within DUF607 and between the transmembrane domains. The DIME motif is a sequence of 23 amino acids that has the sequence: QxGxLAxLTWWxYSWDIMEPVTYF, where letters correspond to actual amino acid residule and "x" represents amino acids that are not conserved within this sequence. Throughout the entire CCDC109B protein there are no other conserved amino acid sequences that are greater than three amino acids in length.[2] The DIME Motif has a hypothesized role in calcium transport and is most likely essential in DUF607.[3]

Post-translational modifications

Phosphorylation sites

The CCDC109B protein contains several likely phosphorylation sites on serine, threonine, and tyrosine residues.[4]

  • Serine Phosphorylation Sites: Amino acid positions 77, 213, 315, and 322.
  • Threonine Phosphorylation Site: Amino acid position 53.
  • Tyrosine Phosphorylation Site: Amino acid position 274.

Sumoylation site

There is one likely sumoylation site within CCDC109B at amino acid residue 306, which is a lysine.[5] This residue is highly conserved among orthologs.

Tertiary structure

Although it is known that CCDC109B is a transmembrane protein the proper folding of its N-terminus and C-terminus is unclear.

Homology

CCDC109B shows conservation in vertebrates, including mammals, birds, reptiles, and amphibians. There appears to be some conservation in earlier organisms such as flies, worms, and plants, but the percent identity is very low and these organisms have many orthologus structures that may not be CCDC109B. The orthologs found in non-vertebrate organisms may also actually be the paralog of CCDC109B which is still producing some identity to CCDC109B.

The table below shows CCDC109B conservation among vertebrate organisms:

File:Phylogenetic Tree for CCDC109B.jpg
Phylogenetic Tree of CCDC109B Orthologs. Length between organisms is related to how closely related they are. Shorter length correlates to more conservation.
Genus Species Organism Common Name Divergence from Humans (MYA) [6] NCBI Protein Accession Sequence Similarity [2] Protein Length
Homo sapiens Humans -- NP_060388.2 100% 336
Pongo abelii Orangutan 15.7 XP_002815099 96% 336
Ailuropoda melanoleuca Panda 94.2 XP_002929388.1 86% 469
Felis catus Domestic Cat 94.2 XP_003985143.1 86% 333
Oryctolagus cuniculus Rabbit 92.3 XP_002717237.1 83% 325
Canis lupus familiaris Domestic Dog 94.2 XP_535692.2 82% 337
Bos taurus Cow 94.1 NP_001068639.1 81% 335
Cricetulus griseus Hamster 92.3 XP_003512344.1 79% 348
Mus musculus Mouse 92.3 NP_080055.2 74% 345
Loxodonta africana Elephant 98.7 XP_003410529.1 74% 428
Gallus gallus Chicken 296 XP_420651.3 63% 345
Anolis carolinensis Lizard 296 XP_003221841.1 59% 319
Sarcophilus harrisii Tasmanian Devil 162.6 XP_003772954.1 59% 342
Xenopus laevis Frog 371.2 NP_001087837.1 55% 319

Paralog of CCDC109B

CCDC109B has a single paralog in the human genome. This paralog is CCDC109A, which is more commonly known as Mitochondrial Calcium Uniporter (MCU)[3] MCU is located in the inner membrane of the mitochondrion and is found as an oligomer that transports calcium ions into the mitochondria. MCU is an essential component of the mitochondrial membrane and sliencing MCU abolishes calcium uptake. The DIME motif, which is also conserved in CCDC109B, is responsible for calcium uptake and a mutation in this region inhibits this function.[3] CCDC109B and MCU share a 43% identity in which the DIME motif is fully conserved.

Expression profile

File:CCDC109B Expression Pattern.png
Expression pattern of CCDC109B. CCDC109B is expressed at high levels in the immune system and also in various blood disorders.

CCDC109B is expressed at high levels in the immune system and the circulatory system.[7] CCDC109B is expressed in B-cells, Dendritic Cells, T-Cells, and Natural Killer Cells. CCDC109B expression is not present in human adipose tissue, adrenal glands, bladder, bone marrow, ear, esophagus, larynx, parathyroid, pituitary gland, spleen, thryroid, trachea, or umbilical cord tissues.[8]

Role in disease

CCDC109B may contribute to a number of diseases including various lymphomas and leukemias.[9] Changes in CCDC109B expression are also present in other diseases such as glioblastomas, Daudi Burkitt's lymphoma, Duchenne muscular dystrophy, breast carcinomas, and promyelocytic leukemia HL-60. CCDC109B may also contribute to atopic dermatitis skin lesions and Job's Syndrome.[10] However, the mechanisms behind the role of CCDC109B in these diseases are unclear and not well characterized through research.

Protein-protein interaction

Transcription factors

CCDC109B has a promoter region that contains sites for transcription factor binding. This promoter region is approximately 500 nucleotides long and is located just prior to the start of translation. Notable transcription factors that bind CCDC109B include:[11]

  • Fork Head Domain Factors (FKHD)
  • Myeloid Zinc Finger 1 Factors (MZF1)
  • Pleomorphic Adenoma Gene (PLAG)
  • C2H2 Zinc Finger Transcription Factors 2 (ZF02)
  • Vertebrate SMAD Family of Transcription Factors (SMAD)
  • Twist Subfamily of Class B bHLH Transcription Factors (HAND)
  • CCAAT/Enhance Binding Protein (CEBP)
  • Nuclear Factor of Activated T-Cells (NFAT)

Cellular proteins

CCDC109B interacts with ZBTB16, which is a zinc-finger transcription factor and has a probable role in protein degradation. CCDC109B's interaction with ZBTB16 was determined by a yeast two-hybrid screen[12] It is still unclear how CCDC109B interacts with ZBTB16.

Other proteins that CCDC109B interact with are currently unknown.

References

  1. ↑ "NCBI AceView CCDC109B". Retrieved October 10, 2016.
  2. ↑ 2.0 2.1 2.2 2.3 "NCBI BLAST".
  3. ↑ 3.0 3.1 3.2 Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Koteliansky V, Mootha VK (2011). "Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter". Nature. 476: 341–345. doi:10.1038/nature10234. PMC 3486726. PMID 21685886.
  4. ↑ "NetPhos".
  5. ↑ "SUMOPlot Analysis Program".
  6. ↑ "Time Tree".
  7. ↑ "GEOProfile CCDC109B".
  8. ↑ "NCBI EST".
  9. ↑ "Genevestigator".
  10. ↑ Rebane A, Zimmermann M, Aab A, Baurecht H, Koreck A, Karelson M, et al. (May 2012). "Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis". J Allergy Clin Immunol. 129 (5): 1297–1306. doi:10.1016/j.jaci.2012.02.020. PMID 22445417.
  11. ↑ "Genomatix ElDorado".
  12. ↑ "GeneCards ZBTB16".

External links

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