Autolysis of Calpain Large Subunit Inducing Irreversible Dissociation of Stoichiometric Heterodimer of Calpain

Abstract

  Calpain, a calcium dependent cysteine protease, consists of a catalytic large subunit and a regulatory small subunit. Two models have been proposed to explain calpain activation: an autolysis model and a dissociation model. In the autolysis model, the autolyzed form is the active species, which is sensitized to Ca²⁺. In the dissociation model, dissociated large subunit is the active species. We have reported that the Ca²⁺ concentration regulates reversible dissociation of subunits. We found further that in chicken μ/m-calpain autolysis of the large subunit induces irreversible dissociation from the small subunit as well as activation. So we could propose a new mechanism for activation of the calpain by combining our findings. Our model insists that autolyzed large subunit remains dissociated from the small subunit even after the removal of Ca²⁺ to keep it sensitized to Ca²⁺. This model could be expanded to other calpains and give a new perspective on calpain activation.