Structure and physiology of calpain, an enigmatic protease.

Calpain is one of the most extensively studied proteinases (1). Although its enzymatic and structural properties have been well characterized, neither the structure-function relationship nor physiological functions are completely understood. In recent years, increasing numbers of molecules showing sequence similarity to calpain have been identified and the concept of a "calpain super family" has become general (2, 3). The term "calpain" originally meant a Ca(2+)-activated, neutral, and intracellular cysteine proteinase, although a proteinase domain similar to that of calpain is a prerequisite for a member of the "calpain super family" (4, 5). The molecular diversity of calpain has attracted interest to its structural and functional transition during evolution. Here we describe the state of current knowledge, progress, and clues to the next phase of calpain research.