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Caspase-8 specificity probed at subsite S4: Crystal structure of the caspase-8-Z-DEVD-cho complex

Journal Article


Abstract


  • Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the downstream executioner caspase-3 is a physiological target. Caspases are cysteine proteases that are specific for substrates with an aspartic acid residue at the P1 position and have an optimal recognition motif that incorporates four amino acid residues N-terminal to the cleavage site. Caspase-8 has been classified as a group III caspase member because it shows a preference for a small hydrophobic residue at the P4 substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a specific group II caspase inhibitor. The structure shows that the inhibitor interacts favourably with the enzyme in subsite S4. Kinetic data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1 nM). In view of this finding, the original classification of caspases into three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue Asp in subsite S4. We propose that the subsite S3 must be considered as an important specificity-determining factor. (C) 2000 Academic Press.

UOW Authors


  •   Blanchard, Helen (external author)

Publication Date


  • 2000

Citation


  • Blanchard, H., Donepudi, M., Tschopp, M., Kodandapani, L., Wu, J. C., & Grütter, M. G. (2000). Caspase-8 specificity probed at subsite S4: Crystal structure of the caspase-8-Z-DEVD-cho complex. Journal of Molecular Biology, 302(1), 9-16. doi:10.1006/jmbi.2000.4041

Scopus Eid


  • 2-s2.0-0034622936

Start Page


  • 9

End Page


  • 16

Volume


  • 302

Issue


  • 1

Abstract


  • Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the downstream executioner caspase-3 is a physiological target. Caspases are cysteine proteases that are specific for substrates with an aspartic acid residue at the P1 position and have an optimal recognition motif that incorporates four amino acid residues N-terminal to the cleavage site. Caspase-8 has been classified as a group III caspase member because it shows a preference for a small hydrophobic residue at the P4 substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a specific group II caspase inhibitor. The structure shows that the inhibitor interacts favourably with the enzyme in subsite S4. Kinetic data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1 nM). In view of this finding, the original classification of caspases into three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue Asp in subsite S4. We propose that the subsite S3 must be considered as an important specificity-determining factor. (C) 2000 Academic Press.

UOW Authors


  •   Blanchard, Helen (external author)

Publication Date


  • 2000

Citation


  • Blanchard, H., Donepudi, M., Tschopp, M., Kodandapani, L., Wu, J. C., & Grütter, M. G. (2000). Caspase-8 specificity probed at subsite S4: Crystal structure of the caspase-8-Z-DEVD-cho complex. Journal of Molecular Biology, 302(1), 9-16. doi:10.1006/jmbi.2000.4041

Scopus Eid


  • 2-s2.0-0034622936

Start Page


  • 9

End Page


  • 16

Volume


  • 302

Issue


  • 1