The property that allows the distinct driving forces to converge on the same activation mechanism seems to be the unusual plasticity of the residues constituting the caspase active site, which, rather unusually for proteases, are predominantly placed on flexible loops and not ordered secondary structure. Only the driving forces are distinct, since the linker segment of pro-caspase 7 blocks ordering of the active site, and upon cleavage the new N- and C-terminal sequences so generated aid in active site stabilization. The same re-ordering of catalytic and substrate binding residues occurs in caspase 7 as seen in caspase 9, so the fundamental mechanism of zymogen activation is equivalent. At cytosolic concentration in human cells, the caspase-3 and -7 zymogens are already dimers, but cleavage within their respective linker segments is required for activation. Once an in initiator caspase has become active, ensuing activation of the executioners is more straightforwardly explained. Salvesen, in Handbook of Cell Signaling (Second Edition), 2010 Executioner Caspases Although the induced-proximity model is consistent with most biochemical data, it offers very little insight regarding the molecular mechanisms of initiator caspase activation under physiological conditions. Following autoproteolytic processing, the prodomains of initiator caspases are also removed by proteolysis to promote a mature enzyme conformation with full catalytic activity ( Figure 2 Chai and Shi, 2014 Pop and Salvesen, 2009). Homodimerzation is believed to be the initial event that triggers activation of initiator caspases that mediate downstream signaling to effector molecules ( Chai and Shi, 2014 Pop and Salvesen, 2009). These conditions favor dimerization which is thought to stimulate the catalytic activity and subsequent autoproteolytic cleavage between the small and large subunits of the catalytic domain ( Figure 2 Chai and Shi, 2014 Pop and Salvesen, 2009). According to this model, dimerization of initiator caspase zymogens occurs when they are brought into close proximity via recruitment into multimeric activation complexes (see section Caspase Activation and Function in Cell Death and Inflammation) resulting in high-local concentrations of zymogen monomers ( Chai and Shi, 2014 Pop and Salvesen, 2009). The current model for activation of initiator caspases is proximity-induced dimerization ( Chai and Shi, 2014).
Long prodomain-containing initiator caspases exist as inactive zymogen monomers in unstressed cells ( Chai and Shi, 2014 Pop and Salvesen, 2009).
0 kommentar(er)
