Is calpain activity regulated by membranes and autolysis or by calcium and calpastatin?

Abstract

Although the Ca(2+)-dependent proteinase (calpain) system has been found in every vertebrate cell that has been examined for its presence and has been detected in Drosophila and parasites, the physiological function(s) of this system remains unclear. Calpain activity has been associated with cleavages that alter regulation of various enzyme activities, with remodeling or disassembly of the cell cytoskeleton, and with cleavages of hormone receptors. The mechanism regulating activity of the calpain system in vivo also is unknown. It has been proposed that binding of the calpains to phospholipid in a cell membrane lowers the Ca2+ concentration, [Ca2+], required for the calpains to autolyze, and that autolysis converts an inactive proenzyme into an active protease. Recent studies, however, show that the calpains bind to specific proteins and not to phospholipids, and that binding to cell membranes does not affect the [Ca2+] required for autolysis. It seems likely that calpain activity is regulated by binding of Ca2+ to specific sites on the calpain molecule, with binding to each site eliciting a response (proteolytic activity, calpastatin binding, etc.) specific for that site. Regulation must also involve an, as yet, undiscovered mechanism that increases the affinity of the Ca(2+)-binding sites for Ca2+.

Metacaspase 2 of Trypanosoma brucei is a calcium‐dependent cysteine peptidase active without processing

“…The calpains, a large family of Ca 2+ -dependent cysteine peptidases, also require significantly higher levels of Ca 2+ for activation in vitro than have been measured intracellularly. It has been postulated that association with cofactors or phospholipids, proteolysis, or a combination of these factors, can lower the Ca 2+ -activation threshold for calpains [20]. Similar mechanisms might exist for MCA2 activation.…”

Ceramide Selectively Decreases Tau Levels in Differentiated PC12 Cells Through Modulation of Calpain I

“…The two major, ubiquitously distributed isoforms calpain I and calpain II are composed of unique 80-kDa subunits and common 30-kDa subunits, and have been classically distinguished because in vitro activation of calpain I requires a lower calcium concentration than calpain II (Mellgren, 1987;Suzuki et al, 1987;Goll et al, 1992). Calpains land II, as well as their endogenous inhibitor calpastatin, are present in neurons; however, their patterns of expression in both mRNA and protein levels differ depending on locations and/or cell types (Hamakubo et al, 1986;Perlmutter et al, 1990;Goto et a!., 1994;Li et al, 1996).…”

Proteolysis of specific muscle structural proteins by mu-calpain at low pH and temperature is similar to degradation in postmortem bovine muscle.

“…The protease m-calpain (for review of calpain, see Goll et al, 1992) has been implicated as the major causative agent for many of the proteolytic changes that occur as meat is aged. Researchers using enzyme caseinolytic activity, SDS-PAGE, and microscopy of digested myofibrils have shown that m-calpain retains at least partial activity under PM conditions of low pH and temperature (Koohmaraie et al, 1986(Koohmaraie et al, , 1987.…”