TMCO4

Transmembrane and coiled-coil domains 4, TMCO4, is a protein in humans that is encoded by the TMCO4 gene. Currently, its function is not well defined. It is transmembrane protein that is predicted to cross the endoplasmic reticulum membrane three times. TMCO4 interacts with other proteins known to play a role in cancer development, hinting at a possible role in the disease of cancer.

Gene
Location of TMCO4 on chromosome 1.[1]

TMCO4 is located on the minus strand of the first chromosome at 1p36.13.[2] The gene consists of 118,172 base pairs stretching from base pair 19,682,213 through 19,800,385.[2] There are no common aliases for TMCO4. Genes CAPZB and LOC105376823 neighbor TMCO4 on chromosome 1.[1] TMCO4 consists of 16 exons.[1]

mRNA

There are twenty mRNA transcript variants (X1-X20) produced through different combinations of sixteen different exons.[3] The most common variant is X1, which includes all exons and spans the entire 118,172 base pairs.[1]

Protein
Schematic illustration of TMCO4 protein. Yellow diamonds represent predicted phosphorylation sites and blue diamonds represent predicted O-linked glycosylation sites.
Four possible secondary structure predictions created by iTASSER software.[1] The first predicted structure on the far left is the most stable, and therefore most probable predicted structure.

Primary sequence

The most common protein encoded by TMCO4 is 634 amino acids in length with accession number XP_011539488.1.[2]

General properties and composition

The molecular weight of TMCO4 is 67.9 kiloDaltons. The isoelectric point is 5.48. As a whole protein, TMCO4 does not have abnormal amino acid distributions. It does have three long stretches of no charge that correspond with the location of the three different transmembrane regions. The first cytosolic domain of TMCO4 does have abnormally high amounts of leucine and glutamic acid and abnormally low amounts of asparagine. The larger lumenal domain of TMCO4 also has an abnormally low amount of asparagine and phenylalanine.

Conceptual translation of TMCO4 page 1. Yellow circles indicate predicted phosphorylation sites and blue circles indicate predicted O-linked glycosylation sites. The highlighting towards the 3' end of the sequence predicts stem loop formations.

Protein features

Two main areas of interest within the TMCO4 protein are the three transmembrane regions and the large Abhydrolase region.[4] The N-terminus of TMCO4 is predicted to be within the cytosol of the cell, and the C-terminus is predicted to be within the lumen of the endoplasmic retiticulum. TMCO4 is also predicted to have a leucine zipper and a large coiled coil domain.[5]

Secondary structure

The secondary structure of TMCO4 is predicted to be dominated by alpha helices based on predictions by iTASSER software.[6]

Post-translational modifications

Many phosphorylation sites were predicted for the two cytosolic regions of TMCO4.[7] O-linked glycosylation sites were predicted to occur in the end of the second lumenal region of TMCO4.[8] These predicted sites can be seen on both the schematic illustration of TMCO4 found above, or in the conceptual translation of TMCO4 found below.

Subcellular localization

TMCO4 is consistently predicted to be located in the endoplasmic reticulum membrane across many homologs.[5]

Conceptual translation of TMCO4 page 2.
Organism Common Name Endoplasmic Reticulum Golgi Mitochondrial Nuclear Plasma Membrane
Homo sapien Human 44.4% 22.2% 22.2% 11.1% -
Mus musculis Mouse 39.1% 4.3% 17.4% 8.7% 21.7%
Xenopus laevis Frog 55.6% - 22.2% 11.1% -
Danio rerio Zebra fish 33.3% 11.1% 11.1% - 22.2%
Callorhinchus milii Australian Ghostshark 33.3% 11.1% 33.3% - 22.2%

Interacting proteins

TMCO4 has been found to interact with many proteins. One protein of interest that TMCO4 interacts with is FLT1.[9] FLT1 is a VEGF receptor[10]. VEGF is known to play a significant role in cancer development. Other proteins that TMCO4 has been experimentally shown to interact with are UBB, UBC, KPTN, and BVLF1.[9] UBB and UBC are polyubiquitins that target molecules for degradation, suggesting that TMCO4 is degraded at some point.[11][12] KPTN is a protein that is essential in neuromorphogenesis.[13] BVLF1 is an Epstein-Barr virus protein.[14]

Homology

Paralogs

TMCO4 does not have any paralogs.

Orthologs

Orthologs to TMCO4 can be found in bacteria, protists, plants, fungi, trichoplax, invertebrates, fish, amphibians, reptiles, birds and mammals.[15] Some of these orthologs can be found in the table below.[15] The orthologs are sorted in descending order of date of evolution from humans and then descending order of percent sequence identity. TMCO4 is a fast evolving gene that has been highly conserved throughout evolution.[15] Regions of TMCO4 that are highly conserved across the orthologs include the various transmembrane domains and the abhydrolase region.

Genus and species Accession number Sequence length Sequence identity Sequence similarity
Homo sapiens (Human) NP_859070.3 634 100% 100%
Papio anubus (Baboon) XP_017813266.1 568 96% 97%
Mus musculus (Mouse) AAH13471.1 631 83% 88%
Ursus maritimus (Polar Bear) XP_008692882.1 608 87% 90%
Gavia stellata (Red-throated loon) XP_009808720.1 610 78% 87%
Python bivittatus (Burmese python) XP_007441490.1 617 70% 83%
Xenopus laevis (Frog) XP_018083828.1 635 75% 87%
Danio rerio (Zebra fish) XP_003201275.2 688 59% 74%
Parasteatoda tepidariorum (Spider) XP_015925328.1 642 56% 74%
Caenorhabditis elegans NP_494812.2 617 42% 59%
Trichoplax adhaerens XP_002107886.1 378 52% 70%
Aspergillus clavatus XP_001275560.1 686 40% 58%
Vibrio parahaemolyticus WP_069539226.1 412 28% 48%

Expression
Expression level of TMCO4 in various tissues page 1.[1]
Expression level of TMCO4 in various tissues page 2.[1]

TMCO4 is highly expressed in many tissues. Highest expression occurs within the prostate, trachea, uterus, small intestine, placenta, thyroid, salivary gland, and adrenal gland. Expression of TMCO4 is predicted to be controlled by many transcription factors.

Clinical Significance

TMCO4 is not currently directly linked to any disease or phenotype. However, interacting with a VEGF receptor may be indicative of a possible role in cancer.

References
  1. "TMCO4 transmembrane and coiled-coil domains 4 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-05-06.
  2. Database, GeneCards Human Gene. "TMCO4 Gene - GeneCards | TMCO4 Protein | TMCO4 Antibody". www.genecards.org. Retrieved 2017-02-18.
  3. [email protected], Danielle Thierry-Mieg and Jean Thierry-Mieg, NCBI/NLM/NIH. "AceView: Gene:TMCO4, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView". www.ncbi.nlm.nih.gov. Retrieved 2017-02-18.
  4. "transmembrane and coiled-coil domain-containing protein 4 [Homo sapien - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-02-18.
  5. "PSORT II Prediction". psort.hgc.jp. Retrieved 2017-05-06.
  6. "I-TASSER server for protein structure and function prediction". zhanglab.ccmb.med.umich.edu. Retrieved 2017-05-06.
  7. "NetPhos 3.1 Server". www.cbs.dtu.dk. Retrieved 2017-05-06.
  8. "NetOGlyc 4.0 Server". www.cbs.dtu.dk. Retrieved 2017-05-06.
  9. "STRING: functional protein association networks". string-db.org. Retrieved 2017-05-06.
  10. "FLT1 - Vascular endothelial growth factor receptor 1 precursor - Homo sapiens (Human) - FLT1 gene & protein". www.uniprot.org. Retrieved 2017-05-06.
  11. "UBC - Polyubiquitin-C precursor - Homo sapiens (Human) - UBC gene & protein". www.uniprot.org. Retrieved 2017-05-06.
  12. "UBB - Polyubiquitin-B precursor - Homo sapiens (Human) - UBB gene & protein". www.uniprot.org. Retrieved 2017-05-06.
  13. "KPTN - Kaptin - Homo sapiens (Human) - KPTN gene & protein". www.uniprot.org. Retrieved 2017-05-06.
  14. "BVLF1 - BVLF1 - Epstein-Barr virus (strain GD1) (HHV-4) - BVLF1 gene & protein". www.uniprot.org. Retrieved 2017-05-06.
  15. "Protein BLAST: search protein databases using a protein query". blast.ncbi.nlm.nih.gov. Retrieved 2017-05-06.
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