Definition
Calpains are calcium dependent non-lysosomal cysteine proteases that are mainly involved in cell cycle progression and cell motility1. Calpastatin is an endogenous inhibitor of calpain that regulates the active enzyme form of calpain1.
Discovery
Calpastatin was first purified to homogeneity from grass prawn muscle through chromatography techniques2.
Classification
Calpastatin belongs to i27 protease inhibitor family3.
Structural Characteristics
It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein4.
Mode of action
Calpastatin binds to domain VI of the calpains through hydrophobic interactions. It has been found that calpastatin calpain interaction is dependent on the intracellular calcium levels and that the interaction is reversible5. Calpastatin not only inhibits the proteolytic activity of calpain but also its interaction with cell membranes5. NMR studies have revealed the structure of calpain/calpastatin complex and this structure has been used to design several small molecule calpain inhibitors5.
Functions
Calapastatin and small molecular calpain inhibitors regulate the cell spreading function of calpain thus influencing reorganization of actin cytoskeleton6. Inhibition of calpains also promotes random migration of cells like neutrophils6. Calpastatin also influences red cell aggregation. Calpain inhibitors are now being used in treating alzheimers disease6.
References
1. Murachi T (1989). Intracellular regulatory system involving calpain and calpastatin. Biochem. Int., 18 (2), 263–94.
2. Shann TJ, Juwen W, Mei-JS, and Shinn ST (2000). Purification and characterization of Calpastatin from Grass Prawn Muscle (Penaeus monodon). J. Agric. Food Chem., 48 (9), 3851–3856.
3. Uemori T, Shimojo T, Asada K, et al. (1990). Characterization of a functional domain of human calpastatin. Biochem. Biophys. Res. Commun., 166 (3), 1485–93.
4. Edon M, Monica A, Roberto S, Roberta De T, Enrico D, Franca S,and Sandro P (2006). Association of Calpastatin with Inactive Calpain – A novel mechanism to control the activation of the protease. J Bio. Chem., 281, 34, 24945-54.
5. Toshihide N and Darrel EG (1991). Binding of Calpain Fragments to Calpastatin. J Bio. Chem., 266, 18, 11842-11950.
6. Santos JF and Anna H (2005). Regulating cell migration: Calpains make the cut. J Cell Science, 118, 3829-3838.