Cysteine requiring aspartate proteases

Activation of Caspases (Cysteine Requiring Aspartate Proteases)... 

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. 

At the center of apoptosis is a family of cysteine proteases, the caspases (cysteine-aspartate proteases) that contain a Cys residue in the catalytic site and cleave their substrates at a consensus (Asp-containing) motif, Asp-Glu-Val-Asp. Caspases display a stringent requirement for Asp in the Pj position of substrates (Nicholson and Thomberry, 1997) and can be classified into three groups based on their substrate specificity (Table 12.8). 

The first class of DUBs discovered, the ubiquitin C-terminal Aydrolases (UCHs), is a relatively small class vith only four members in humans and one in budding yeast. UCHs are cysteine proteases related to the papain family of cysteine proteases. Most UCHs consist entirely of a catalytic core that has a molecular mass of about 25 kDa, although Bapl and UCH37 have C-terminal extensions [21, 22], All UCHs have a highly conserved catalytic triad consisting of the active-site cysteine, histidine, and aspartate residues that are absolutely required for function [23]. 

Classincation of the Proteases. The classification of the proteases is based on their mechanism of catalysis (4), The four primary classes of proteases are the serine, aspartic, cysteine, and metalloproteases (5). This classification is based on the primary functional group found in the en me s active site. There are likely to be other proteases eventually characterized which will not precisely fit into this categorization scheme and additional categories will be needed. One example of a potential new category is the ATP-dependent proteinases (6), a group of proteinases which require ATP for activity. 

Execution of apoptosis in mammalian cells requires the coordinated action of several aspartate-specific cysteine proteases, called caspases, which are responsible for the cleavage of key enzymatic and structural... 

---