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  • Review Article
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Molecular mechanisms of caspase regulation during apoptosis

Nature Reviews Molecular Cell Biology volume 5, pages 897–907 (2004)Cite this article

Key Points

  • The molecular mechanism of activation for a representative effector caspase, caspase-7, is revealed by the conformational changes of the active site that take place after the activation cleavage. The essence of this mechanism is the provision of the L2′ loop, which is released by the activation cleavage and provides crucial support for the conformation of the active site.

  • The molecular mechanism of inhibitor of apoptosis (IAP)-mediated inhibition of an effector caspase primarily involves the occupation of the caspase active site by an extended peptide fragment that immediately precedes the second baculoviral IAP repeat (BIR) domain, BIR2, of XIAP, c-IAP1 or c-IAP2.

  • The BIR3 domain of XIAP inhibits caspase-9, an initiator caspase, by sequestering caspase-9 in a monomeric state, so that the L2′ loop cannot be provided by the adjacent monomer and the active site cannot be productively formed. This inhibition is dependent on, and initiated by, the binding between a conserved surface groove of the BIR3 domain of XIAP and the N-terminal tetrapeptide (Ala-Thr-Pro-Phe) of the small subunit of caspase-9.

  • The viral protein p35 inhibits a caspase through the formation of a covalent thioester bond between the catalytic residue Cys360 of caspase-8 and Asp87 of p35, which follows caspase-mediated cleavage of the reactive-site loop of p35 after Asp87.

  • The XIAP-mediated inhibition of caspase-9 can be countered effectively by SMAC/DIABLO, which uses its N-terminal tetrapeptide (Ala-Val-Pro-Ile) to compete with caspase-9 for binding to the same conserved surface groove of the BIR3 domain of XIAP. In Drosophila melanogaster, the caspase-9 orthologue Dronc is suppressed by Diap1 through an interaction that involves an internal peptide fragment of Dronc and the conserved surface groove of the BIR2 domain of Diap1. The pro-apoptotic proteins Reaper, Hid, Grim and Sickle use their N-terminal peptide fragments (which are similar to the SMAC/DIABLO tetrapeptide) to compete with Dronc for binding to the same conserved surface groove, thereby removing the Diap1-mediated negative regulation of Dronc.

  • The exact mechanisms for the removal of effector-caspase inhibition remain to be defined. The prevailing model, which is supported by biochemical data, is that the binding of effector caspases by SMAC/DIABLO creates steric hindrance that dissociates the interaction between IAPs and the effector caspases.

  • To gain a comprehensive picture of the molecular mechanisms of caspase regulation, future efforts should be directed at understanding the activation of initiator caspases and caspase pathways in Drosophila melanogaster and Caenorhabditis elegans.

Abstract

Caspases, which are the executioners of apoptosis, comprise two distinct classes, the initiators and the effectors. Although general structural features are shared between the initiator and the effector caspases, their activation, inhibition and release of inhibition are differentially regulated. Biochemical and structural studies have led to important advances in understanding the underlying molecular mechanisms of caspase regulation. This article reviews these latest advances and describes our present understanding of caspase regulation during apoptosis.

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Figure 1: Apoptotic caspases in mammals, fruitflies and nematodes.
Figure 2: A conserved apoptotic pathway in nematodes, mammals and fruitflies.
Figure 3: Structural features of caspases.
Figure 4: Molecular mechanism of procaspase-7 activation.
Figure 5: IAPs in mammals and fruitflies.
Figure 6: Molecular mechanism of IAP-mediated inhibition of effector caspases.
Figure 7: Molecular mechanism of XIAP-mediated inhibition of caspase-9.
Figure 8: Molecular mechanism of p35-mediated inhibition of caspase-8.
Figure 9: SMAC/DIABLO-mediated removal of caspase-9 inhibition by XIAP.
Figure 10: Molecular mechanism of RHG-mediated removal of Dronc suppression by Diap1.

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Acknowledgements

We would like to thank N. Yan for help with figure preparation and members of the Shi laboratory for discussion. This research is supported by the National Institutes of Health.

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Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, 08544, New Jersey, USA

    Stefan J. Riedl & Yigong Shi

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  1. Stefan J. Riedl
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Correspondence to Yigong Shi.

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DATABASES

Entrez

ced-3

ced-4

ced-9

egl-1

Flybase

Damm

Dcp1

Decay

Diap2

Dredd

Drice

Dronc

Grim

Hid

Reaper

Sickle

Strica

Thread

Swiss-Prot

AIF

APAF1

Apollon

BAK

BCL2

BID

caspase-2

caspase-3

caspase-6

caspase-7

caspase-8

caspase-9

caspase-10

c-IAP1

c-IAP2

CrmA

cytochrome c

DIABLO

EndoG

FADD

Fas

FasL

HTRA2

ICE

ILP2

ML-IAP

NAIP

p35

XIAP

FURTHER INFORMATION

Nature Reviews poster 'Apoptosis Pathways and Drug Targets'

The PyMOL Molecular Graphics System

Glossary

PRODOMAIN

The N-terminal amino-acid sequence of a caspase. Unlike other proteases, the removal of the prodomain is not required for the activation of caspases. Rather, the presence of the prodomain is indispensable to the activation of initiator caspases.

ZYMOGEN

The proteolytically inactive precursor of a protease.

APOPTOSOME

A large protein complex that comprises cytochrome c and APAF1, and forms in the presence of ATP or dATP. The apoptosome recruits pro-caspase-9 and results in the allosteric activation of caspase-9.

DEATH LIGAND

An extracellular growth factor that triggers an apoptotic response in cells.

DEATH RECEPTOR

The cell-surface receptor for the death ligand. A death receptor contains an extracellular ligand-binding domain and an intracellular death domain.

BH3-ONLY

BCL2 homology (BH) domain-3 only. Sequence alignment among the BCL2-family proteins has identified four BH domains, BH1–BH4. The BH3-only members are pro-apoptotic.

BCL2 FAMILY

A family of proteins that all contain at least one BCL2 homology (BH) region. The family is divided into anti-apoptotic multidomain proteins (such as BCL2 and BCL-XL), which contain four BH domains (BH1, BH2, BH3, BH4), pro-apoptotic multidomain proteins (for example, BAX and BAK), which contain BH1, BH2 and BH3, and the pro-apoptotic BH3-only protein family (such as BID, BIM and PUMA).

SERPIN

A family of serine-protease inhibitors. Serpin inactives protease by deformation of the active site.

RHG PROTEINS

Named after the fruitfly Reaper, Hid and Grim proteins. The name now refers to a larger family of pro-apoptotic proteins in fruitflies that share an N-terminal inhibitor of apoptosis (IAP)-binding tetrapeptide motif.

N-END RULE

A ubiquitin-dependent pathway that targets proteins for degradation through their destabilizing N-terminal residues.

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Riedl, S., Shi, Y. Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5, 897–907 (2004). https://doi.org/10.1038/nrm1496

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  • DOI: https://doi.org/10.1038/nrm1496

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