Triadin

Last updated
TRDN
Identifiers
Aliases TRDN , CPVT5, TDN, TRISK, triadin, CARDAR
External IDs OMIM: 603283; MGI: 1924007; HomoloGene: 38137; GeneCards: TRDN; OMA:TRDN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10345

76757

Ensembl

ENSG00000186439

ENSMUSG00000019787

UniProt

Q13061

E9Q9K5

RefSeq (mRNA)

NM_001251987
NM_001256020
NM_001256021
NM_001256022
NM_006073

Contents

NM_029726
NM_001364696
NM_001364697

RefSeq (protein)

NP_084002
NP_001351625
NP_001351626

Location (UCSC) Chr 6: 123.22 – 123.64 Mb Chr 10: 32.96 – 33.35 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Triadin, also known as TRDN, is a human gene [5] associated with the release of calcium ions from the sarcoplasmic reticulum triggering muscular contraction through calcium-induced calcium release. Triadin is a multiprotein family, arising from different processing of the TRDN gene on chromosome 6. [6] It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section [7] [8] and it forms a quaternary complex with the cardiac ryanodine receptor (RYR2), calsequestrin (CASQ2) and junctin proteins. [7] [8] [9] [10] The luminal (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca2+ receptors. [7] [8] [10] Triadin is also able to sense luminal Ca2+ concentrations by mediating interactions between RYR2 and CASQ2. [9] Triadin has several different forms; Trisk 95 and Trisk 51, which are expressed in skeletal muscle, and Trisk 32 (CT1), which is mainly expressed in cardiac muscle. [11]

Interactions

TRDN has been shown to interact with RYR1. [12] [13] [14] [15]

Triadin is required to physically link the RYR2 and CASQ2 proteins, so that RYR2 channel activity can be regulated by CASQ2. [16] The linkage of RYR2 with CASQ2 occurs via highly charged luminal sections of Triadin [10] that are characterized as alternating positively and negatively charged amino acids, known as the KEKE motif. [8] [9] [10] [17]

Luminal concentration levels of Ca2+ are sensed by CSQ, and this information is transmitted to RyR via Triadin. At low luminal Ca2+ concentrations, Triadin is bound to both RYR2 and CASQ2, so that CSQ prevents RYR2 from opening. At high luminal Ca2+ concentrations, Ca2+ binding sites on CASQ2 become occupied with Ca2+, leading to a weakened interaction between CASQ2 and Triadin. This removes CASQ2's ability to have an inhibitory effect on the RYR2 channel activity. As more Ca2+ binding sites on CASQ2 become occupied, there is an increasing probability of the RYR2 channel being able to open. Eventually, CASQ2 completely dissociates from Triadin and the RYR2 channel becomes completely uninhibited, although Triadin remains bound to RYR2 at all luminal concentrations of Ca2+. [16]

Relation to catecholaminergic polymorphic ventricular tachycardia

Most mutations that result in CPVT are found in RYR2 or CASQ2 genes, however a third of CPVT patients have no mutations in either of these proteins, making a mutation in Triadin the most likely cause [18] Because Triadin is necessary in the regulation of Ca2+ release by the RyR channel during cardiac contraction, a mutation that prevents Triadin from being formed will make CASQ2 unable to inhibit the RYR2 channel activity, allowing Ca2+ leaks and the development of CPVT. [18]

A deletion of amino acids in the TRDN gene can result in an early stop codon. [18] A premature stop codon can either prevent the gene from being translated into the Triadin protein, or can result in a shortened, nonfunctional Triadin protein. [18] A replacement of the amino acid Arginine for the amino acid Threonine at position 59 of the TRDN gene (pT59R) causes instability of Triadin, leading to degradation of the protein. [18] Any of these naturally occurring mutations result in an absence of functional Triadin protein, resulting in CPVT in patients. [18]

Related Research Articles

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Calsequestrin is a calcium-binding protein that acts as a calcium buffer within the sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the sarcoplasmic reticulum after a muscle contraction, even though the concentration of calcium in the sarcoplasmic reticulum is much higher than in the cytosol. It also helps the sarcoplasmic reticulum store an extraordinarily high amount of calcium ions. Each molecule of calsequestrin can bind 18 to 50 Ca2+ ions. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface. Two forms of calsequestrin have been identified. The cardiac form Calsequestrin-2 (CASQ2) is present in cardiac and slow skeletal muscle and the fast skeletal form Calsequestrin-1(CASQ1) is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation. When calcium binds there is a structural change whereby the alpha-helical content of the protein increases from 3 to 11%. Both forms of calsequestrin are phosphorylated by casein kinase 2, but the cardiac form is phosphorylated more rapidly and to a higher degree. Calsequestrin is also secreted in the gut where it deprives bacteria of calcium ions..

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000186439 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000019787 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: TRDN triadin".
  6. ↑ Thevenon, D.; Smida-Rezgui, S.; Chevessier, F.; Groh, S.; Henry-Berger, J.; Romero, N. B.; Villaz, M.; De Waard, M; Marty, I (2003). "Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51". Biochem. Biophys. Res. Commun. 303 (12): 669–675. doi:10.1016/s0006-291x(03)00406-6. PMID   12659871.
  7. 1 2 3 Kobayashi, Y. M.; Jones, L. R. (1999). "Identification of triadin 1 as the predominant triadin isoform expressed in mammalian myocardium". J. Biol. Chem. 274 (40): 28660–28668. doi: 10.1074/jbc.274.40.28660 . PMID   10497235.
  8. 1 2 3 4 Jones, L. R.; Zhang, L.; Sanborn, K.; Jorgensen, A. O.; Kelley., J. (1995). "Purification, primary structure, and immunological characterization of the 26-kDa calsequestrin binding protein (junctin) from cardiac junctional sarcoplasmic reticulum". J. Biol. Chem. 270 (51): 30787–30796. doi: 10.1074/jbc.270.51.30787 . PMID   8530521.
  9. 1 2 3 Zhang, L.; Kelley, J.; Schmeisser, G.; Kobayashi, Y. M.; Jones, L. R. (1997). "Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane". J. Biol. Chem. 272 (37): 23389–23397. doi: 10.1074/jbc.272.37.23389 . PMID   9287354.
  10. 1 2 3 4 Kobayashi, Y. M.; Alseikhan, B. A.; Jones, L. R. (2000). "Localization and characterization of the calsequestrin-binding domain of triadin 1. Evidence for a charged beta-strand in mediating the protein-protein interaction". J. Biol. Chem. 275 (23): 17639–17646. doi: 10.1074/jbc.M002091200 . PMID   10748065.
  11. ↑ Marty, I.; Fauré, J.; Fourest-Lieuvin, A.; Vassilopoulos, S.; Oddoux, S.; Brocard, J. (2009). "Triadin: what possible function 20 years later?". J. Physiol. 587 (13): 3117–3121. doi:10.1113/jphysiol.2009.171892. PMC   2727022 . PMID   19403623.
  12. ↑ Lee, Jae Man; Rho Seong-Hwan; Shin Dong Wook; Cho Chunghee; Park Woo Jin; Eom Soo Hyun; Ma Jianjie; Kim Do Han (Feb 2004). "Negatively charged amino acids within the intraluminal loop of ryanodine receptor are involved in the interaction with triadin". J. Biol. Chem. 279 (8). United States: 6994–7000. doi: 10.1074/jbc.M312446200 . ISSN   0021-9258. PMID   14638677.
  13. ↑ Caswell, A H; Motoike H K; Fan H; Brandt N R (Jan 1999). "Location of ryanodine receptor binding site on skeletal muscle triadin". Biochemistry. 38 (1). United States: 90–7. doi:10.1021/bi981306+. ISSN   0006-2960. PMID   9890886.
  14. ↑ Guo, W; Campbell K P (Apr 1995). "Association of triadin with the ryanodine receptor and calsequestrin in the lumen of the sarcoplasmic reticulum". J. Biol. Chem. 270 (16). United States: 9027–30. doi: 10.1074/jbc.270.16.9027 . ISSN   0021-9258. PMID   7721813.
  15. ↑ Groh, S; Marty I; Ottolia M; Prestipino G; Chapel A; Villaz M; Ronjat M (Apr 1999). "Functional interaction of the cytoplasmic domain of triadin with the skeletal ryanodine receptor". J. Biol. Chem. 274 (18). United States: 12278–83. doi: 10.1074/jbc.274.18.12278 . ISSN   0021-9258. PMID   10212196.
  16. 1 2 Gyorke, I.; Hester, N.; Jones, L. R.; Gyorke, S. (2004). "The Role of Calsequestrin, Triadin, and Junctin in Conferring Cardiac Ryanodine Receptor Responsiveness to Luminal Calcium". Biophysical Journal. 86 (4): 2121–2128. Bibcode:2004BpJ....86.2121G. doi:10.1016/S0006-3495(04)74271-X. PMC   1304063 . PMID   15041652.
  17. ↑ Shin, D. W.; Ma, J.; Kim, D. H. (2000). "The asp-rich region at the carboxyl-terminus of calsequestrin binds to Ca2+ and interacts with triadin". FEBS Lett. 486 (2): 178–182. doi:10.1016/S0014-5793(00)02246-8. PMID   11113462. S2CID   3135618.
  18. 1 2 3 4 5 6 Roux-Buisson, N.; Cacheux, M.; Fourest-Lieuvin, A.; Fauconnier, J.; Brocard, J.; Denjoy, I.; Durand, P.; Guicheney, P.; Kyndt, F.; Leenhardt, A.; Le Marec, H.; Lucet, V.; Mabo, P.; Probst, V.; Monnier, N.; Ray, P. F.; Santoni, E.; Tremeaux, P.; Lacampagne, A.; Faure, J.; Lunardi, J.; Marty, I. (2012). "Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human". Human Molecular Genetics. 21 (12): 2759–2767. doi:10.1093/hmg/dds104. PMC   3363337 . PMID   22422768.

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