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, 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 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 molecular mechanism for the "induced proximity" hypothesis (Salvesen and Dixit, 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.
Jaroszewski
L
L
The Burnham Institute, La Jolla, California 92037, USA.
Rychlewski
L
L
Reed
J C
JC
Godzik
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D017173:Caenorhabditis elegans / Q000737:chemistry; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D015801:Helminth Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; D015801:Helminth Proteins; D010446:Peptide Fragments; D011506:Proteins; D000255:Adenosine Triphosphate