Calcium-activated neutral protease (calpain) system: structure, function, and regulation.

DE Croall, GN Demartino - Physiological reviews, 1991 - journals.physiology.org
DE Croall, GN Demartino
Physiological reviews, 1991journals.physiology.org
It has been over 25 years since the first descriptions of a soluble Ca2+-activated neutral
proteolytic activity (103, 122, 215). Since that time this activity has been identified in a wide
variety of tissues and species and has been implicated in many cellular functions. Calcium-
activated neutral proteolytic activity is now known to be accounted for by at least two distinct
enzymes (69,197,222,270,327,328). It is generally agreed that these enzymes are
proenzymes that are regulated, at least in vitro, by Ca2+ binding and autoproteolytic …
It has been over 25 years since the first descriptions of a soluble Ca2+-activated neutral proteolytic activity (103, 122, 215). Since that time this activity has been identified in a wide variety of tissues and species and has been implicated in many cellular functions. Calcium-activated neutral proteolytic activity is now known to be accounted for by at least two distinct enzymes (69,197,222,270,327,328). It is generally agreed that these enzymes are proenzymes that are regulated, at least in vitro, by Ca2+ binding and autoproteolytic modification. Furthermore, the identification of two specific regulatory proteins, an inhibitor and a stimulator (55, 64, ZOO, 221), indicates that these proteases are part of a complex, highly regulated, Ca2’-dependent proteolytic system widely distributed among eucaryotic cells. These Ca2+-activated neutral proteases (CANPs, calpains, or Ca2+-dependent proteases; EC 3.42217) have received considerable attention in recent years for a variety of reasons. For example, it is now recognized that intracellular protein degradation is an important mechanism for the regulation of levels of individual proteins as well as overall growth and atrophy of tissues (97, 98, 304). Considerable evidence suggests that much of the intracellular protein degradation occurs by nonlysosomal mechanisms (72,118), and the CANPs represent one of the few well-characterized nonlysosomal proteolytic systems of mammalian cells. Although there is no clear or direct evidence that CANPs catalyze bulk intracellular protein degradation, these enzymes have often been implicated as participants in various pathologies associated with altered protein metabolism and/or altered Ca2+ homeostasis, including ischemic injury to muscle or nerve, cell death, and degenerative diseases. In our judgement these remain open questions. However, two lines of evidence suggest that CANPs may play a regulatory rather than a degradative role in cellular protein metabolism. First, Ca2+ is well established as an important regulator of many key cellular functions, including cell growth, secretion, and cellular response to hormones (82, 286, 287). Although the exact biochemical mechanisms by which Ca2’influences these functions are still not well defined, many Ca2’-binding proteins, such as the CANPs, are likely to be involved. The second argument for the regulatory functions of these enzymes is that they appear only to modify (and not degrade) numerous cytoskeletal proteins, receptor
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