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A Primer on Caspase Mechanisms


A Primer on Caspase Mechanisms

Monica L Gonzalez Ramirez et al. Semin Cell Dev Biol.


Caspases belong to a diverse clan of proteolytic enzymes known as clan CD with highly disparate functions in cell signaling. The caspase members of this clan are only found in animals, and most of them orchestrate the demise of cells by the highly distinct regulated cell death phenotypes known as apoptosis and pyroptosis. This review looks at the mechanistic distinctions between the activity and activation mechanisms of mammalian caspases compared to other members of clan CD. We also compare and contrast the role of different caspase family members that program anti-inflammatory and pro-inflammatory cell death pathways.

Keywords: Apoptosis; Gasdermin; Protease; Pyroptosis; Regulated cell death.


Figure 1
Figure 1. Peptidase clan CD dendrogram illustrating evolutionary relationships of human caspases and their homologs
Apoptotic caspases are featured in green hues, inflammatory caspases in red, and the remaining four human members of peptidase clan CD are in blue. Caspases-2 and −14 are uncolored and unassigned, as they have primary roles unassociated with apoptosis or inflammation. Pseudoproteases, FLIP and caspase-12, are proteins with the characteristic fold but mutations in their catalytic machinery render them proteolytically incompetent.
Figure 2
Figure 2. Domain structures of human caspases
Apical caspases contain domains that serve to recruit the zymogens to activation complexes through homotypic protein interactions – DED (Death Effector Domain) and CARD (Caspase Recruitment Domain). Effector caspases lack these recruitment domains, and are activated by cleavage within the catalytic domain by apical caspases. Cleavage within the catalytic domain is obligatory for effector caspase activation, but dispensable for apical caspase activation.
Figure 3
Figure 3. Distinct activation mechanisms of apical and effector caspases
Apical caspase-8 and effector caspase-7 shown as examples, based on the crystal structures reported in PDB codes 2K7Z, 3KJQ, 1GQF, 1F1J. Apical caspases undergo proximity-induced dimerization within activation complexes. Sometimes they also undergo cleavage within the catalytic domain to yield short segments of secondary structure that stabilize the resulting dimer (red circles). Cleavage of the pre-formed zymogen dimer of caspase-7 (red arrowheads) results in activation with an analogous further stabilization of the dimer (red circles).

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