Calsequestrin. Structure, function, and evolution

Calsequestrin is the major Ca²⁺ binding protein in the sarcoplasmic reticulum (SR), serves as the main Ca²⁺ storage and buffering protein and is an important regulator of Ca²⁺ release channels in both skeletal and cardiac muscle. It is anchored at the junctional SR membrane through interactions with membrane proteins and undergoes reversible polymerization with increasing Ca²⁺ concentration. Calsequestrin provides high local Ca²⁺ at the junctional SR and communicates changes in luminal Ca²⁺ concentration to Ca²⁺ release channels, thus it is an essential component of excitation-contraction coupling. Recent studies reveal new insights on calsequestrin trafficking, Ca²⁺ binding, protein evolution, protein-protein interactions, stress responses and the molecular basis of related human muscle disease, including catecholaminergic polymorphic ventricular tachycardia (CPVT). Here we provide a comprehensive overview of calsequestrin, with recent advances in structure, diverse functions, phylogenetic analysis, and its role in muscle physiology, stress responses and human pathology.