Interdimer processing mechanism of procaspase-8 activation

David W. Chang, Zheng Xing, Vanessa L. Capacio, Marcus E. Peter, Xiaolu Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

191 Scopus citations

Abstract

The execution of apoptosis depends on the hierarchical activation of caspases. The initiator procaspases become autoproteolytically activated through a less understood process that is triggered by oligomerization. Procaspase-8, an initiator caspase recruited to death receptors, is activated through two cleavage events that proceed in a defined order to generate the large and small subunits of the mature protease. Here we show that dimerization of procaspase-8 produces enzymatically competent precursors through the stable homophilic interaction of the procaspase-8 protease domain. These dimers are also more susceptible to processing than individual procaspase-8 molecules, which leads to their cross-cleavage. The order of the two interdimer cleavage events is maintained by a sequential accessibility mechanism: the separation of the large and small subunits renders the region between the large subunit and prodomain susceptible to further cleavage. In addition, the activation process involves an alteration in the enzymatic properties of caspase-8; while procaspase-8 molecules specifically process one another, mature caspases only cleave effector caspases. These results reveal the key steps leading to the activation of procaspase-8 by oligomerization.

Original languageEnglish (US)
Pages (from-to)4132-4142
Number of pages11
JournalEMBO Journal
Volume22
Issue number16
DOIs
StatePublished - Aug 15 2003

Keywords

  • Apoptosis
  • CD95(Fas/APO-1)
  • Caspase-8
  • Interdimer cleavage
  • Oligomerization

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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