Review Article | Published:

New insights into apoptosome structure and function

Cell Death & Differentiationvolume 25pages11941208 (2018) | Download Citation

Abstract

The apoptosome is a platform that activates apical procaspases in response to intrinsic cell death signals. Biochemical and structural studies in the past two decades have extended our understanding of apoptosome composition and structure, while illuminating the requirements for initiator procaspase activation. A number of studies have now provided high-resolution structures for apoptosomes from C. elegans (CED-4), D. melanogaster (Dark), and H. sapiens (Apaf-1), which define critical protein interfaces, including intra and interdomain interactions. This work also reveals interactions of apoptosomes with their respective initiator caspases, CED-3, Dronc and procaspase-9. Structures of the human apoptosome have defined the requirements for cytochrome c binding, which triggers the conversion of inactive Apaf-1 molecules to an extended, assembly competent state. While recent data have provided a detailed understanding of apoptosome formation and procaspase activation, they also highlight important evolutionary differences with functional implications for caspase activation.

Graphical Abstract

Comparison of the CARD/CARD disks and apoptosomes formed by CED-4, Dark and Apaf-1. Cartoons of the active states of the CARD-CARD disks, illustrating the two CED-4 CARD tetrameric ring layers (CED4a and CED4b; top row) and the binding of 8 Dronc CARDs and between 3-4 pc-9 CARDs, to the Dark and Apaf-1 CARD disk respectively (middle and lower rows). Ribbon diagrams of the active CED-4, Dark and Apaf-1 apoptosomes are shown (right column).

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Edited by G. Melino

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Acknowledgements

This caspase work in our laboratory (LD, SK) is supported by the National Health and Medical Research Council (NHMRC) of Australia project grants 1021456 and 1043057, a Cancer Council Collaborative Research Fellowship to LD and a NHMRC Senior Principal Research Fellowship to SK (1103006). Apoptosome structure/function studies were supported by NIGMS GM63834 (CWA).

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Affiliations

  1. Center for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA, 5001, Australia

    • Loretta Dorstyn
    •  & Sharad Kumar
  2. Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA, 02118, USA

    • Christopher W. Akey

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The authors declare that they have no competing interests.

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Correspondence to Loretta Dorstyn or Sharad Kumar.

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https://doi.org/10.1038/s41418-017-0025-z