Sandbox/ caspase-3 regulation: Difference between revisions
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V266E is a mutation that improves caspase-3 activity dramatically. Even in the uncleavable procaspase-3 (D5A, D26A, D175A), V266E mutant zymogen is also pseudo-activated (60-fold activity). Interestingly, V266E does not change a lot conformation around active site in the active caspase-3. Based on the crystal structure, L2’ loop is partially disorder at 185’-180’. In the homology model of zymogen caspase-3, the catalytic C163 is buried in the dimer interface. E266, which is longer than V266, could push the ILB to the exposed position to make catalytic part is similar as active caspase-3. This active procaspase-3 cannot be inhibited by endogenous XIAP like normal cleaved caspase-3. So it provides us an option for apoptosis stimuli with intrinsic efficiency. | V266E is a mutation that improves caspase-3 activity dramatically. Even in the uncleavable procaspase-3 (D5A, D26A, D175A), V266E mutant zymogen is also pseudo-activated (60-fold activity). Interestingly, V266E does not change a lot conformation around active site in the active caspase-3. Based on the crystal structure, L2’ loop is partially disorder at 185’-180’. In the homology model of zymogen caspase-3, the catalytic C163 is buried in the dimer interface. E266, which is longer than V266, could push the ILB to the exposed position to make catalytic part is similar as active caspase-3. This active procaspase-3 cannot be inhibited by endogenous XIAP like normal cleaved caspase-3. So it provides us an option for apoptosis stimuli with intrinsic efficiency. | ||
It was found recently that many other mutant residues on the dimer interface might play an important role on inhibition of caspase-3 through manipulating the hydrogen bond or remote talking across whole dimer. For instance, V266H inhibit caspase-3 activity totally, but the double mutation Y197C/V266H the activity is rescued. Structural evidence demonstrates that H266 clashes with Y197, which prevent R164 insert in the dimer interface, which is indispensable to form correct L2 conformation and catalytic loop bundle. Y197C mutation | It was found recently that many other mutant residues on the dimer interface might play an important role on inhibition of caspase-3 through manipulating the hydrogen bond or remote talking across whole dimer. For instance, V266H inhibit caspase-3 activity totally, but the double mutation Y197C/V266H the activity is rescued. Structural evidence demonstrates that H266 clashes with Y197, which prevent R164 insert in the dimer interface, which is indispensable to form correct L2 conformation and catalytic loop bundle. Y197C mutation relieves this clash. | ||
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====Post translational Modification==== | ====Post translational Modification==== | ||
S-nitrosylation of cysteine also regulates activity of caspase-3 in response of NO in the cell (Maejima, Adachi et al. 2005). As the previous discovery of nitosylated catalytic cysteine in the other caspases, S-nitrosylation directly inhibits the function of C163 of caspase-3. This kind of regulation is sufficiently strong and is a new anti-cancer pathway. For example, induced NO stress could definitely inhibit the myocardial apoptosis at the treatment of DOX. | |||
====Natural Inhibitors==== | ====Natural Inhibitors==== | ||