Crystallisation and structural details of Ca2+ induced conformational changes in the EF-hand domain VI of Calpain

Abstract

Calpains are calcium-regulated neutral cysteine proteases that include ubiquitous, as well as tissue-specific, isoforms. The ubiquitous isoforms, μ- and m-calpains are intracellular, nonlysosomal proteases (1). The tissue-specific isoforms include calpain 3, which is found in skeletal muscle, and stomach-specific nCL–2 (2). The calpains catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction, although definitive physiological roles are not yet ascertained. They are also thought to contribute to the tissue damage that follows ischemia and reperfusion in conditions such as stroke and cardiac infarct (3,4), stimulating a search for specific and clinically acceptable inhibitors aimed at both the active site and also the Ca2+-binding domains (5). The calpains are heterodimers that consist of an 80-kDa catalytic subunit (the large subunit), and a 30-kDa regulatory subunit (the small subunit).