Target protease specificity of the viral serpin CrmA. Analysis of five cascapses

Qiao Zhou, Scott Snipas, Kim Ortht, Marta Muzio, Vishva M. Dixit, Guy S. Salvesen

Research output: Contribution to journalArticlepeer-review

Abstract

When ectopically expressed in animal cells, cytokine response modifier A (CrmA), a product of the cowpox virus, prevents programmed cell death initiated by a variety of stimuli. Since CrmA is a proteinase inhibitor, its target is probably a protease that promotes cell death. The identification of this target is crucial in delineating essential regulation points that modulate the apoptotic program. We have compared the kinetics of interaction of CrmA with five proteases that may play a role in apoptosis. Four of the proteases, all members of the caspase family, are inhibited with widely different rates and affinities ranging over 5 orders of magnitude. One is not inhibited at all under the experimental conditions. CrmA is quite selective in its ability to inhibit caspases, showing the highest affinity for interleukin-1β-converting enzyme and the second highest for the caspase FLICE (K(i) = 0.95 nM), identified as a component of the intracellular signaling complex recruited by ligation of the death receptor Fas. On the basis of comparative inhibitor kinetics, we propose that CrmA is unlikely to inhibit the caspases Yama, Mch2, or LAP3 in vivo but that its inhibition of FLICE is of a magnitude for this protease to he a key target of CrmA during Fas-mediated apoptosis. Therefore, our results support the hypothesis that FLICE catalyzes a crucial step in the promotion of cell death.

Original languageEnglish
Pages (from-to)7797-7800
Number of pages4
JournalJournal of Biological Chemistry
Volume272
Issue number12
DOIs
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Target protease specificity of the viral serpin CrmA. Analysis of five cascapses'. Together they form a unique fingerprint.

Cite this