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Review
. 2022 Aug 1;14(8):a041020.
doi: 10.1101/cshperspect.a041020.

Caspase Activation and Inhibition

Douglas R Green  1
Affiliations
Review

Caspase Activation and Inhibition

Douglas R Green. Cold Spring Harb Perspect Biol. .
No abstract available

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
The structures of inactive and active caspase-7. The arginine (R) in the specificity loop is indicated, as is the cysteine–histidine (C–H) catalytic dyad. (Left, PDB 1K86 [Chai et al. 2001]; right, PDB 1GOF [Reidl et al. 2001a].)
Figure 2.
Figure 2.
Close-up view of caspase-7 activation. Three loops mediate caspase-7 active site assembly: the specificity loop (red), a neighboring loop that draws the specificity loop into position (blue), and the linker between the large and small subunits (green). Structures are the inactive zymogen (left), the inhibitor-bound enzyme (center), and the active enzyme (right). (Left, PDB 1K86 [Chai et al. 2001]; center, PDB 1F1J [Wei et al. 2000]; right, PDB 1GOF [Reidl et al. 2001a].)
Figure 3.
Figure 3.
Cytotoxic lymphocyte killing a target (cell). The target cells are stained red, and the cell at left is undergoing apoptosis. Green: cytotoxic granules in the cytotoxic lymphocyte. (Reproduced from Bleakley 2008, ©2008 with permission from Lippincott, Williams & Wilkins. Image kindly provided by Dr. I.S. Goping, University of Alberta.)
Figure 4.
Figure 4.
Simplified scheme of cytotoxic granule killing.
Figure 5.
Figure 5.
Initiator caspases can be activated by induced proximity. Kosmotropic salts, which cause protein aggregation, activate initiator caspases that remain active after the salt is removed. If the cleavage sites between the protease subunits are made uncleavable by mutation, the salts can still activate the enzyme, but the enzyme becomes inactive when the salts are removed.
Figure 6.
Figure 6.
General apoptotic pathways.
Figure 7.
Figure 7.
Representative death folds. Although different death folds do not have sequence similarity, they are structurally related. Each has six globular helical bundles, shown here colored gray to dark purple from the amino to carboxyl termini.2 (Left to right, PDB 1DDF [Huang et al. 1996]; PDB 1CWW [Day et al. 1999]; PDB 1PN5 [Hiller et al. 2003]; PDB 1A1Z [Eberstadt et al. 1998].)
Figure 8.
Figure 8.
The transition from inactive to active caspase-9. When caspase-9 is dimerized, the specificity-determining loop (red) is brought into position by a loop (blue) from the other monomer. Cleavage of the region between the protease subunits (green) is not necessary for activation. Only one site in the dimer can form at a time: One is inactive (left) and the other is active (right). (Reproduced with permission from Fuentes-Prior and Salvesen 2004, ©The Biochemical Society.)
Figure 9.
Figure 9.
Pyroptosis. Cells die in a caspase-1-dependent manner, indicated by arrows. (Reprinted by permission from Macmillan Publishers Ltd.: Fernandes-Alnemri et al. 2007, ©2007.)
Figure 10.
Figure 10.
Caspase-12 and beyond in mammals. Lengths shown are arbitrary. Caspases-15, -17, and -18 are not found in humans, and caspase-12 is frequently not found in humans. Caspases-11 (mouse) and -13 (cow) are homologs of caspase-5 and caspase-3, respectively, and are not shown.
Figure 11.
Figure 11.
Caspase inhibitors. The peptide portion is shown with a single-letter code.
Figure 12.
Figure 12.
Caspase-3 bound to the inhibitor zVAD-fmk. (PDB 1CP3 [Mittl et al. 1997].)
Figure 13.
Figure 13.
Caspase inhibitors block the morphological features of apoptosis. Appearance of different cell types treated to induce apoptosis in the presence or absence of the caspase inhibitor zVAD-fmk. (Upper) Bright-field images of fibroblasts. (Lower) Electron micrographs of tumor cells. (Images courtesy of Dr. Nigel Waterhouse, Mater Medical Research Institute, Brisbane, Australia.)
Figure 14.
Figure 14.
Loss of DIAP1 causes apoptosis. Extensive cell death, staining green, is not seen in a wild-type embryo (left), but is observed in a DIAP1 mutant embryo (right). (Reprinted from Wang et al. 1999, ©1999 with permission from Elsevier.)
Figure 15.
Figure 15.
Some IAPs.
Figure 16.
Figure 16.
XIAP binds to the active sites in caspase-3. Only the BIR2 domain in XIAP (green) is shown. (Purple circles indicate zinc atoms that coordinate the folding of XIAP.) (PDB 1I3O [Riedl et al. 2001b].)
Figure 17.
Figure 17.
Caspases and IAPs in apoptosis.
See this image and copyright information in PMC

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References

    1. Green DR. 2022a. Caspases and their substrates. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041012 - DOI - PMC - PubMed
    1. Green DR. 2022b. The burial: clearance and consequences. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041087 - DOI - PMC - PubMed
    1. Green DR. 2022c. Inflammasomes and other caspase-activation platforms. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041061 - DOI - PMC - PubMed
    1. Green DR. 2022d. The death receptor pathway of apoptosis. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041053 - DOI - PMC - PubMed
    1. Green DR. 2022e. The mitochondrial pathway of apoptosis, Part 1: MOMP and beyond. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041038 - DOI - PMC - PubMed

FIGURE CREDITS

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