Caspase-3 Regulatory Mechanisms: Difference between revisions
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<scene name='Caspase-3_Regulatory_Mechanisms/Scene2_nospin_labels/1'>L2 and L2'</scene> | <scene name='Caspase-3_Regulatory_Mechanisms/Scene2_nospin_labels/1'>L2 and L2'</scene> | ||
== Regulation of Caspase-3== | |||
<StructureSection load='1dq8' size='350' side='right' caption='Structure of HMG-CoA reductase (PDB entry [[1dq8]])' scene=''> | |||
Anything in this section will appear adjacent to the 3D structure and will be scrollable. | |||
</StructureSection> | |||
===Exosite and Allosteric Site=== | |||
Caspases have similar structure of active site. Exosite that could be utilized to improve activity has been found in caspase-7 (Boucher, Blais et al. 2012). Caspase-7 also has an inhibitory allosteric site that could bind with small molecule FICA, presenting a zymogen-like conformation (Hardy, Lam et al. 2004). | |||
Although there is no evident exosite found in caspase-3, some allosteric sites, (most of which are located on the dimer interface,) has been studied by mutagenesis. Some of mutant residues can modulate the activity of caspase-3 or even procaspase-3. The procaspase-3 was detected only little activity because the orientation of ILA (prematured L2 loop) and ILB loop cannot form an active site pocket (Bose, Pop et al. 2003). | |||
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’. 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, like V266H, Y197C, E124A. | |||
====Post translational Modification==== | |||
====Natural Inhibitors==== | |||
X-linked inhibitor of apoptosis proteins (XIAP) contains the second baculovirus IAP repeat domain (BIR2) targeting caspase-3 and caspase-7. | |||
Reference: | |||
Bose, K., C. Pop, et al. (2003). "An uncleavable procaspase-3 mutant has a lower catalytic efficiency but an active site similar to that of mature caspase-3." Biochemistry 42(42): 12298-12310. | |||
Boucher, D., V. Blais, et al. (2012). "Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis." Proc Natl Acad Sci U S A 109(15): 5669-5674. | |||
Hardy, J. A., J. Lam, et al. (2004). "Discovery of an allosteric site in the caspases." Proc Natl Acad Sci U S A 101(34): 12461-12466. | |||