Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1

Hongxu Qin, Srinivasa M. Srinivasula, Geng Wu, Teresa Fernandes-Alnemri, Emad S. Alnemri and Yigong Shi ()
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Hongxu Qin: Department of Chemistry and
Srinivasa M. Srinivasula: Kimmel Cancer Center, Thomas Jefferson University
Geng Wu: Department of Chemistry and
Teresa Fernandes-Alnemri: Kimmel Cancer Center, Thomas Jefferson University
Emad S. Alnemri: Kimmel Cancer Center, Thomas Jefferson University
Yigong Shi: Princeton University

Nature, 1999, vol. 399, issue 6736, 549-557

Abstract: Abstract Caspase-9-mediated apoptosis (programmed cell death) plays a central role in the development and homeostasis of all multicellular organisms. Mature caspase-9 is derived from its procaspase precursor as a result of recruitment by the activating factor Apaf-1. The crystal structures of the caspase-recruitment domain of Apaf-1 by itself and in complex with the prodomain of procaspase-9 have been determined at 1.6 and 2.5 Å resolution, respectively. These structures and other evidence reveal that each molecule of Apaf-1 interacts with a molecule of procaspase-9 through two highly charged and complementary surfaces formed by non-conserved residues; these surfaces determine recognition specificity through networks of intermolecular hydrogen bonds and van der Waals interactions. Mutation of the important interface residues in procaspase-9 or Apaf-1 prevents or reduces activation of procaspase-9 in a cell-free system. Wild-type, but not mutant, prodomains of caspase-9 completely inhibit catalytic processing of procaspase-9. Furthermore, analysis of homologues from Caenorhabditis elegans indicates that recruitment of CED-3 by CED-4 is probably mediated by the same set of conserved structural motifs, with a corresponding change in the specificity-determining residues.

Date: 1999
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DOI: 10.1038/21124

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