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

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Abstract
Fold recognition algorithm FFAS ( 1 , Protein Sci, 2000;9:232–241) was used to match the nucleotide‐binding adaptor shared by APAF‐1, certain R gene products and CED‐4 (NB‐ARC domain) to the structure of the D2 domain of N‐ethylemaleimide‐Sensitive Fusion Protein and the δ` subunit of clamp loader of DNA polymerase III. The predicted structure consists of the p‐loop ATP‐binding domain, followed by two α‐helical domains that regulate the oligomerization process. This prediction suggests a detailed molecular mechanism for the “induced proximity” hypothesis ( 2 , Proc Natl Acad Sci USA 1999;96:10964–10967) for CED3/caspase‐9 activation by CED4/APAF‐1 complex. According to this model, the ATP binding acts as a trigger in CED‐4 oligomerization and the helical domain immediately following the ATP‐binding domain provides additional mechanisms for regulation of the oligomerization process. This model explains most of known experimental data about CED‐4‐mediated caspase activation and, at the same time, suggest experiments that could test this hypothesis. Proteins 2000;39:197–203.