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Review
. 2009 Aug 14;284(33):21777-21781.
doi: 10.1074/jbc.R800084200. Epub 2009 May 26.

Human caspases: activation, specificity, and regulation

Cristina Pop  1 , Guy S Salvesen  1
Affiliations
Review

"V体育平台登录" Human caspases: activation, specificity, and regulation

Cristina Pop et al. J Biol Chem. .

Abstract

Caspases are intracellular proteases that propagate programmed cell death, proliferation, and inflammation. Activation of caspases occurs by a conserved mechanism subject to strict cellular regulation. Once activated by a specific stimulus, caspases execute limited proteolysis of downstream substrates to trigger a cascade of events that culminates in the desired biological response. Much has been learned of the mechanisms that govern the activation and regulation of caspases, and this minireview provides an update of these areas. We also delineate substantial gaps in knowledge of caspase function, which can be approached by techniques and experimental paradigms that are currently undergoing development VSports手机版. .

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Figures

FIGURE 1.
FIGURE 1.
A, caspase organization. A prodomain precedes the catalytic domain, composed of two covalently linked subunits. Sites for (auto)proteolysis at Asp residues are indicated. B, activation mechanisms. Initiators are monomers that activate by prodomain-mediated dimerization. Executioners are dimers that activate by cleavage of intersubunit linkers. Following activation, additional proteolytic events mature the caspases to more stable forms, prone to regulation.
FIGURE 2.
FIGURE 2.
A, activation pathways and substrates. An oligomeric protein platform activates an apical caspase (casp), which then cleaves specific caspases. The apoptotic apical caspases require an intermediary step through the direct activation of downstream caspases, creating a two-step pathway that amplifies the apoptotic signal and allows for additional regulation points. A few caspase substrates are shown, but many are yet to be discovered. Caspase inhibitors (shown in boxes) regulate the activation pathways. IL, interleukin; ICAD, inhibitor of caspase-activated DNase; PARP, poly(ADP-ribose) polymerase; Rb, retinoblastoma protein; PKCδ, protein kinase Cδ. B, substrate specificity of caspases. The figure plots amino acid preferences in the P4–P1′ positions of caspases. The total height of each position is proportional to sequence conservation, whereas the height of residues in each position plots the relative frequency of each amino acid at the position (see the WebLogo web site). The Casp-3 and Casp-8 panels summarize peptide libraries exploring the P4–P1′ substrate primary specificity determinants and reveal little overlap between caspase-3 and -8 (taken from data in Refs. and 35). The Apoptotic cells panel shows caspase substrates from natural proteins cleaved in apoptotic cells, revealing an almost total dropout in specificity of the P4 site, implying that selectivity for natural substrates may fail to obey the simplistic rules established with synthetic peptide library substrates (taken from data in Ref. 18).
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