TCAIM explained

TCAIM is a protein that in humans is encoded by the TCAIM gene[1] [2] (T-cell activation inhibitor, mitochondrial).

Gene

The gene is located on chromosome 3, at position 3p21.31, and is 71,333 bases long. A graphic of the image is show below in Fig.1.2 The TCAIM protein is 496 residues long and weighs 57925 Da. It exists in four different isoforms. TCAIM is highly conserved among different species, but no homologies to protein families of known functions were discovered.[3]

Transcript

There are 8 alternatively spliced exons, which encode 4 transcript variants. The primary transcript, which is 3520 bp, is well conserved among orthologs, with the human isoform 1 having high identity with orthologous proteins. The X1 transcript contains 11 exons, which yield a polypeptide that is 496 amino acid residues in length.[4]

Protein

General properties

Property Pre-Protein Cleaved Protein Mature Protein
Amino Acid Length 496 470 470
Isoelectric Point 8.7 8.5 8.2-8.6
Molecular Weight 58 kdal 55 kdal ~55-57

The isoelectric point is significantly greater than average for human proteins (6.81).[5]

Structure

Shown to the right is a predicted tertiary structure of the protein. It is composed mostly of long alpha-helices with several coil regions and strands dispersed throughout the length of the protein. The ends of the protein consist of coil regions opposite the N- and C- terminal ends.

Expression

TCAIM is moderately expressed (50-75%) in most tissues in the body.[6] However, a study on NCBI GEO discussing the effect of disease states on TCAIM mRNA expression found that protein expression was actually elevated in HPV positive tissues compared to the HPV negative tissues. Another study found that TCAIM expression was elevated in individuals with Type 2 diabetes and insulin resistance. The expression of TCAIM seems to be contingent on the specific disease state in a variety of cases.[7]

Subcellular localization

The protein contains a mitochondrial signal peptide localizing it to the mitochondrial matrix.[8] Analysis via the EXPASY localization software[9] confirmed this finding. The high isoelectric point of the Human protein provides further evidence for the mitochondrial localization due to the high pH of the mitochondrial matrix.

Post-translational modifications

Cleavage sites

The protein is initially cleaved to remove the 26 amino acids from the N-terminus. This represents a signal peptide after it is localized to the mitochondrion.[8]

Phosphorylation

There are a number of predicted phosphorylation sites, as see in the figure to the right. Serine residues are more likely to undergo phosphorylation than threonine or tyrosine residues.

O-linked glycosylation

Shown to the right are a number of predicted o-linked sites. None have been experimentally determined thus far.

Homology and Evolution

Homologs

An alignment of Homo sapiens TCAIM and Danio rerio (Zebrafish) homologs was performed using the SDSC workbench. There is approximately 55% identity between the two orthologs, with a global alignment score of 1817. The two orthologs are consistently similar throughout the entirety of their sequences. The differences between the two genes is due seemingly random segments of non-conserved and semiconserved residues scattered throughout the two alignments. This difference may be due to the non-relatedness between the two organisms.[10]

Evolutionary history

TCAIM diverged much quicker than cytochrome C, but slightly slower than fibrinogen.[11]

Function

Not much is known about the function; it is surmised that this protein may play a role in apoptosis of T-cells. TCAIM may play a role in the innate immune signaling via the mitochondria.[12]

Clinical significance

A research study was performed by Vogel et al. They previously found that TCAIM is highly expressed in grafts and tissues of tolerance-developing transplant patients and that the protein is localized in the mitochondria. In this study, they found that TCAIM interacts with and is regulated by CD11c(+) dendritic cells.[12] Another article by Hendrikson et. el briefly mentions TCAIM. They found that genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression.[3] The third article is another research that finds evidence that TCAIM (along with mitochondrial genes) could be used as a marker in patients to predict whether they could accept an allograft or reject it.[13]

Further reading

Notes and References

  1. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc Natl Acad Sci U S A . 99 . 26 . 16899–903 . Dec 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . free .
  2. Web site: Entrez Gene: C3orf23 chromosome 3 open reading frame 23.
  3. Hendrickson SL, Lautenberger JA, Chinn LW, Malasky M, Sezgin E, Kingsley LA, Goedert JJ, Kirk GD, Gomperts ED, Buchbinder SP, Troyer JL, O'Brien SJ . Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression . PLOS ONE . 5 . 9 . e12862 . 2010 . 20877624 . 2943476 . 10.1371/journal.pone.0012862 . 2010PLoSO...512862H . free .
  4. Web site: TCAIM T cell activation inhibitor, mitochondrial [Homo sapiens (human)] - Gene - NCBI.
  5. Kozlowski, Lukasz P. "Proteome-pI - Proteome Isoelectric Point Database statistics". isoelectricpointdb.org. Retrieved 2017-04-30.
  6. Uhlén M et al, 2015. Tissue-based map of the human proteome. SciencePubMed: 25613900 DOI: 10.1126/science.1260419
  7. Web site: GDS161 / RC_N95260_at.
  8. Web site: TCAIM Gene - GeneCards | TCAIM Protein | TCAIM Antibody.
  9. Web site: ExPASy: SIB Bioinformatics Resource Portal - Categories.
  10. Myers EW, Miller W . Optimal alignments in linear space . Computer Applications in the Biosciences . 4 . 1 . 11–7 . 1988 . 3382986 . 10.1093/bioinformatics/4.1.11 . 10.1.1.107.6989 .
  11. Web site: UCSC Genome Browser Home.
  12. Vogel SZ, Schlickeiser S, Jürchott K, Akyuez L, Schumann J, Appelt C, Vogt K, Schröder M, Vaeth M, Berberich-Siebelt F, Lutz MB, Grütz G, Sawitzki B . TCAIM decreases T cell priming capacity of dendritic cells by inhibiting TLR-induced Ca2+ influx and IL-2 production . Journal of Immunology . 194 . 7 . 3136–46 . 2015 . 25750433 . 10.4049/jimmunol.1400713 . free .
  13. Sawitzki B, Bushell A, Steger U, Jones N, Risch K, Siepert A, Lehmann M, Schmitt-Knosalla I, Vogt K, Gebuhr I, Wood K, Volk HD . Identification of gene markers for the prediction of allograft rejection or permanent acceptance . American Journal of Transplantation . 7 . 5 . 1091–102 . 2007 . 17456197 . 10.1111/j.1600-6143.2007.01768.x . 20348485 . free .

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