tailieunhanh - Báo cáo khoa học: The structural basis of calpain behavior

Calpains are intracellular Ca 2+ -regulated cysteine pro-teases which mediate regulatory cleavage of specific substrates. They cover a broad range of physiological functions including proteolysis of molecules involved in cytoskeletal organization, the cell cycle, signal trans-duction, apoptosis, and protein renewal during growth and tissue regeneration. Originally found in mamma-lian skeletal muscle then in numerous organisms inclu-ding protists and plants, their expression is ubiquitous [1,2]. | FEBS Journal MINIREVIEW SERIES The structural basis of calpain behavior Yves Benyamin UMR5539 EPHE-CNRS-UM2 cc107 Université de Montpellier II France Calpains are intracellular Ca2 -regulated cysteine proteases which mediate regulatory cleavage of specific substrates. They cover a broad range of physiological functions including proteolysis of molecules involved in cytoskeletal organization the cell cycle signal transduction apoptosis and protein renewal during growth and tissue regeneration. Originally found in mammalian skeletal muscle then in numerous organisms including protists and plants their expression is ubiquitous 1 2 . Among the 14 members of the calpain gene family with different expression patterns in tissue development two ubiquitous isoforms microcalpain p-cal-pain or calpain 1 and milli-calpain m-calpain or calpain 2 have been the focus of three decades of intensive characterization. In vitro analysis has shown that the Ca2 concentration required for optimal activity is 5-50 M for calpain 1 and mM for cal-pain 2. A large range of substrates and a common inhibitor calpastatin also found in the nucleus were identified. Knowledge of the 3D structure of Ca2 -free calpain 2 and a chimeric I m-calpain has provided mechanistic concepts for understanding their allosteric regulation 3-6 . Briefly Fig. 1 ubiquitous calpains have an 80-kDa catalytic subunit backbone representation and a 28-kDa regulatory subunit space-filled representation which functions as a chaperone to stabilize the 80-kDa structure. The critical importance of the 28-kDa subunit which is common to the two calpains was shown by the fact that transgenic mice with a knock-out gene die at an early stage of embryonic development. This subunit contains a mobile hydrophobic segment dashed purple segment and a penta EF-hand domain DV and DVI respectively . In the 80-kDa subunit the N-terminal segment DI interacts with DVI which anchors DII catalytic domain to the 28-kDa subunit. DII DIIa .