The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinct activities

Chu Chiao Wu, Sunhee Lee, Srinivas Malladi, Miao Der Chen, Nicholas J. Mastrandrea, Zhiwen Zhang, Shawn B. Bratton

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

According to dogma, initiator caspases are activated through proximity-induced homodimerization, but some studies infer that during apoptosis caspase-9 may instead form a holoenzyme with the Apaf-1 apoptosome. Using several biochemical approaches, including a novel site-specific crosslinking technique, we provide the first direct evidence that procaspase-9 homodimerizes within the apoptosome, markedly increasing its avidity for the complex and inducing selective intramolecular cleavage at Asp-315. Remarkably, however, procaspase-9 could also bind via its small subunit to the NOD domain in Apaf-1, resulting in the formation of a heterodimer that more efficiently activated procaspase-3. Following cleavage, the intersubunit linker (and associated conformational changes) in caspase-9-p35/p12 inhibited its ability to form homo- and heterodimers, but feedback cleavage by caspase-3 at Asp-330 removed the linker entirely and partially restored activity to caspase-9-p35/p10. Thus, the apoptosome mediates the formation of caspase-9 homo- and heterodimers, both of which are impacted by cleavage and contribute to its overall function.

Original languageEnglish (US)
Article number13565
JournalNature communications
Volume7
DOIs
StatePublished - Nov 24 2016

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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