Cathepsin proteolytic mechanism

Effector caspases are activated by a transactivation mechanism, which is characterized by the catalytic action of a mature caspase on a procaspase (Thornberry et al., 1997 Earnshaw et al., 1999 Slee et al., 1999). Nevertheless, their activation can also occur by the action of other proteases. Granzyme B, a serine-protease, also has proteolytic specificity for aspartic acid residues. It is able to cleave and directly activate caspase 3 (Darmon et al., 1995). Cathepsin B, a lysosomal protease, cleaves and activates procaspase 11 (Schotte et al., 1998). 

Despite considerable research, the mechanisms of protein turnover are still unclear. However, several aspects of this process are now known. Proteins are degraded by proteolytic enzymes found throughout the cell. These include the cytoplasmic Ca2+-acti-vated calpains and the lysosomal cathepsins. In addition, ubiquina-tion is now believed to have a major role in protein turnover. In ubiquination, illustrated in Figure 15A, several molecules of a small 76-residue eukaryotic protein called ubiquitin are covalently attached to some proteins destined for degradation. Once a pro-... 

Second, of several proteases that are known to participate in peptide/protein hydrolysis, the cysteine and aspartic proteases, also known as cathepsins, constitute a majority of the endosomal/lysosomal proteolytic machinery. These enzymes are often synthesized in an inactive form requiring excision of the pro-domain facilitated by other proteases or autocatalytic mechanisms activated by acidic pH. Cathepsins seem to have originally evolved to catabolize both internalized and endogenous proteins crucial for cellular homeostasis, autophagy, apoptosis, and antigen presentation. The optimal pH range for enzymatic activity of cathepsins ranges from 5.0 to 6.5, as is the case with endosomes/lysosomes. 

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