ATP-activated oligomerization as a mechanism for apoptosis regulation: Fold and mechanism prediction for CED-4

Fold recognition algorithm FFAS (Rychlewski et al., Protein Sci, 2000;9:232 -241) was used to match the nucleotide-binding adaptor shared by APAF-1, ce rtain R gene products and CFD-4 (NB-ARC domain) to the structure of the D2 domain of N-ethylemaleimide-Sensitive Fusion Protein and the delta' subunit of clamp loader of DNA polymerase III, The predicted structure consists of the p-loop ATP-binding domain, followed by two alpha-helical domains that regulate the oligomerization process. This prediction suggests a detailed m olecular mechanism for the "induced proximity" hypothesis (Salvesen and Dix it, Proc Natl Acad Sci USA 1999;96: 10964-10967) for CED3/caspase-9 activat ion by CED4/APAF-1 complex, According to this model, the ATP binding acts a s a trigger in CED-4 oligomerization and the helical domain immediately fol lowing the ATP-binding domain provides additional mechanisms for regulation of the oligomerization process. This model explains most of known experime ntal data about CED-4-mediated caspase activation and, at the same time, su ggest experiments that could test this hypothesis. (C) 2000 Wiley-Liss, Inc .