Calsequestrin is a

calcium-binding protein Calcium-binding proteins are proteins that participate in calcium cell signaling pathways by binding to Ca2+, the calcium ion that plays an important role in many cellular processes. Calcium-binding proteins have specific domains that bind to calc ...

that acts as a calcium buffer within the sarcoplasmic reticulum. The protein helps hold calcium in the

cisterna A cisterna (: cisternae) is a flattened membrane vesicle found in the endoplasmic reticulum and Golgi apparatus. Cisternae are an integral part of the packaging and modification processes of proteins occurring in the Golgi. Function Proteins begi ...

of the sarcoplasmic reticulum after a

muscle contraction Muscle contraction is the activation of Tension (physics), tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in musc ...

, 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 In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is cal ...

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 In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

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.

Cardiac calsequestrin

Cardiac calsequestrin (CASQ2) plays an integral role in cardiac regulation.

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s in the cardiac calsequestrin gene have been associated with

cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beat ...

and sudden death. CASQ2 is thought to have a role in regulating cardiac excitation-contraction coupling and calcium-induced calcium release (CICR) in the heart, as overexpression of CASQ2 has been shown to substantially raise the magnitude of cell-averaged I_CA-induced calcium transients and spontaneous calcium sparks in isolated heart cells. Furthermore, CASQ2 modulates the CICR mechanism by lengthening to process to functionally recharge the sarcoplasmic reticulum's calcium ion stores. A lack of or mutation in CASQ2 has been directly associated with

catecholaminergic polymorphic ventricular tachycardia Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur du ...

(CPVT). A mutation can have a significant effect if it disrupts the linear polymerization ability of CASQ2, which directly accounts for its high-capacity to bind Ca²⁺. In addition, the hydrophobic core of domain II appears to be necessary for CASQ2's function, because a single amino acid mutation that disrupts this hydrophobic core directly leads to molecular aggregates, which are unable to respond to calcium ions.

References

External links

GeneReviews/NCBI/NIH/UW entry on Catecholaminergic Polymorphic Ventricular Tachycardia
* {{InterPro content, IPR001393 Protein families Endoplasmic reticulum resident proteins

Cardiac calsequestrin

See also

References

Further reading

External links