Activation of zymogens Sample Clauses

Activation of zymogens. Proteases can be regulated by various ways, including transcriptional regulation, activation of zymogens, blockage by endogenous inhibitors, targeting to specific compartments, and post-translational modifications such as glycosylation, metal binding, disulfide bridging, proteolysis, and degradation (208). However, a common way of protease activation is by cleavage of zymogens. In fact, many proteases including digest proteases (pepsin, chymotrypsin, trypsin), blood clotting proteases, caspases, are activated by limited proteolysis of zymogens (208). The activation of zymogens can be either autoproteolytic (115) or proteolyzed by other proteases (86). In some cases it requires additional factors or platforms, such as the apoptosome which mediates the activation of caspase zymogens (86). Some pro-domains have no known function, such as digestive proteases, but some pro-domains of zymogens contain recognition sites for interaction with substrates or cofactors, determining localization of proteases and how the zymogen is activated (208). For example, the pro-domain of the initiator caspase-8 contains the death effector domain (DED) that recruits caspase-8 to Fas-associated protein with death domain (FADD). The recruitment allows dimerization of caspase-8, which is monomeric in the dormant state. The dimeric caspase-8 is activated through induced fit and will cleave the pro-domain. Caspase-7 is an executioner caspase and exists as a dimer in dormant state already, but the dimeric caspase-7 has little protease activity. Instead, the dimeric caspase-7 is cleaved by initiator caspases at the consensus caspase cleavage site located at the linker domain. The N-terminal pro-domain of caspase-7 is much shorter than initiator caspases and does not appear to interact with other proteins but is still required for the activation (31).