Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16254-61. doi: 10.1073/pnas.1418000111. Epub 2014 Oct 13.

Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome.

Author information

1
Ministry of Education Protein Science Laboratory, Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; and.
2
Department of Chemistry, Tsinghua University, Beijing 100084, China.
3
Ministry of Education Protein Science Laboratory, Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; and shi-lab@tsinghua.edu.cn.

Abstract

Autocatalytic activation of an initiator caspase triggers the onset of apoptosis. In dying cells, caspase-9 activation is mediated by a multimeric adaptor complex known as the Apaf-1 apoptosome. The molecular mechanism by which caspase-9 is activated by the Apaf-1 apoptosome remains largely unknown. Here we demonstrate that the previously reported 1:1 interaction between Apaf-1 caspase recruitment domain (CARD) and caspase-9 CARD is insufficient for the activation of caspase-9. Rather, formation of a multimeric CARD:CARD assembly between Apaf-1 and caspase-9, which requires three types of distinct interfaces, underlies caspase-9 activation. Importantly, an additional surface area on the multimeric CARD assembly is essential for caspase-9 activation. Together, these findings reveal mechanistic insights into the activation of caspase-9 by the Apaf-1 apoptosome and support the induced conformation model for initiator caspase activation by adaptor complexes.

KEYWORDS:

CARD; apoptosis; caspase activation; induced proximity; mechanism

PMID:
25313070
PMCID:
PMC4246342
DOI:
10.1073/pnas.1418000111
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center