Calsequestrin

Abstract

The contraction/relaxation of the muscle cell is controlled by the transient increase/decrease of Ca 2+ concentration. A large fraction of this Ca 2+ is stored in and released from the sarcoplasmic reticulum (SR) by the presence of high concentrations of an acidic protein, calsequestrin, in the lumen of the junctional terminal cisternae of SR. Calsequestrin binds and releases large quantities of Ca 2+ ion rapidly: about 40 to 50 ions per molecule with a binding constant of approximately 1 mM under physiological conditions. The cation binding by calsequestrin is nonspecific and the Ca 2+ binding sites incorporate the numerous acidic residues that comprise over one‐third of the total residues. The crystal structure of calsequestrin shows that it is made up of three domains, each with a thioredoxin fold. Ca 2+ ions are bound on the protein surface and between domains. Two distinct dimerization contacts in calsequestrin crystals suggested a mechanism for Ca 2+ regulation resulting from the occurrence of coupled Ca 2+ binding and protein polymerization. Ca 2+ ‐induced formation of one contact was proposed to lead to dimerization followed by Ca 2+ ‐induced formation of the second contact to bring about polymerization. Strong cooperative calcium binding accompanies the polymerization of calsequestrin into insoluble, extended, and often needle‐like structures. The polymerization of calsequestrin also provides a highly charged surface onto which calcium is adsorbed. A sparingly soluble ion such as Ca 2+ would tend to spread over the surface of the polymer, forming a readily exchangeable film. The propensity of Ca 2+ ‐bound calsequestrin to form linear structures would make Ca 2+ dissociation and diffusion a more rapid event.