Triadin, also known as TRDN, is a human
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
associated with the release of calcium ions from the
sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kep ...
triggering muscular contraction through
calcium-induced calcium release. Triadin is a multiprotein family, arising from different processing of the TRDN gene on
chromosome 6
Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total ...
. It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section
and it forms a quaternary complex with the cardiac
ryanodine receptor
Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons.
There are three major isoforms of the ryanodine receptor, which are found in different tissu ...
(
RYR2
Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the ''RYR2'' gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major med ...
), calsequestrin (
CASQ2) and
junctin proteins.
The
luminal (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca
2+ receptors.
Triadin is also able to sense luminal Ca
2+ concentrations by mediating interactions between RYR2 and CASQ2.
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.
Interactions
TRDN has been shown to
interact
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with
RYR1
Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is one of a class of ryanodine receptors and a protein found primarily in skeletal muscle
Skeletal muscles (commonly ...
.
Triadin is required to physically link the
RYR2
Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the ''RYR2'' gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major med ...
and CASQ2 proteins, so that RYR2 channel activity can be regulated by CASQ2.
The linkage of RYR2 with CASQ2 occurs via highly charged luminal sections of Triadin
that are characterized as alternating positively and negatively charged amino acids, known as the KEKE motif.
Luminal concentration levels of Ca
2+ are sensed by CSQ, and this information is transmitted to
RyR via Triadin. At low luminal Ca
2+ concentrations, Triadin is bound to both RYR2 and CASQ2, so that CSQ prevents RYR2 from opening. At high luminal Ca
2+ concentrations, Ca
2+ binding sites on CASQ2 become occupied with Ca
2+, 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 Ca
2+ 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 Ca
2+.
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
Because Triadin is necessary in the regulation of Ca
2+ 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 Ca
2+ leaks and the development of
CPVT.
A deletion of
amino acids in the TRDN gene can result in an early
stop codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon ( nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in ...
.
A premature
stop codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon ( nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in ...
can either prevent the
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
from being translated into the Triadin protein, or can result in a shortened, nonfunctional Triadin protein.
A replacement of the amino acid
Arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...
for the amino acid
Threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
at position 59 of the TRDN gene (pT59R) causes instability of Triadin, leading to degradation of the protein.
Any of these naturally occurring mutations result in an absence of functional Triadin protein, resulting in CPVT in patients.
References
Further reading
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External links
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* {{UCSC gene details, TRDN