Abstract

Calpain (Cp) is a calcium (Ca2+)‐dependent cysteine protease. Activation of the major isoforms of Cp, CpI and CpII, are required for a number of important cellular processes including adherence, shape change and migration. The current concept that cytoplasmic Cp locates and associates with its regulatory subunit (Rs) and substrates as well as translocates throughout the cell via random diffusion is not compatible with the spatial and temporal constraints of cellular metabolism. The novel finding that Cp and Rs function relies upon tenacious hydrophobic interactions with organelle membranes offers a unifying explanation for the paradoxical and puzzling features of Cp activation and regulation such as how nM concentrations of intracellular Ca2+ can activate Cp molecules requiring μM to mM concentrations of Ca2+ for in vitro activation, and how this protease can spatially and temporally locate specific substrates and translocate throughout the cell. We hypothesize that Cp and its regulatory moieties associate with organelles to facilitate the activation of this protease resulting in the cleavage of substrates and aid in its translocation throughout the cell. BioEssays 28: 850–859, 2006. © 2006 Wiley Periodicals, Inc.