A structure of the human apoptosome at 12.8 A resolution provides insights into this cell death platform

Structure. 2005 Nov;13(11):1725-35. doi: 10.1016/j.str.2005.09.006.

Abstract

Apaf-1 and cytochrome c coassemble in the presence of dATP to form the apoptosome. We have determined a structure of the apoptosome at 12.8 A resolution by using electron cryomicroscopy and single-particle methods. We then docked appropriate crystal structures into the map to create an accurate domain model. Thus, we found that seven caspase recruitment domains (CARDs) form a central ring within the apoptosome. At a larger radius, seven copies of the nucleotide binding and oligomerization domain (NOD) associate laterally to form the hub, which encircles the CARD ring. Finally, an arm-like helical domain (HD2) links each NOD to a pair of beta propellers, which bind a single cytochrome c. This model provides insights into the roles of dATP and cytochrome c in assembly. Our structure also reveals how a CARD ring and the central hub combine to create a platform for procaspase-9 activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Apoptotic Protease-Activating Factor 1 / chemistry*
  • Apoptotic Protease-Activating Factor 1 / metabolism
  • Caspase 9 / metabolism
  • Cell Death / physiology
  • Crystallography, X-Ray
  • Cytochromes c / chemistry*
  • Cytochromes c / metabolism
  • Deoxyadenine Nucleotides / metabolism*
  • Humans
  • Protein Structure, Tertiary
  • Sequence Analysis, Protein

Substances

  • Apoptotic Protease-Activating Factor 1
  • Deoxyadenine Nucleotides
  • Cytochromes c
  • Caspase 9