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

Proteins. 2000 May 15;39(3):197-203. doi: 10.1002/(sici)1097-0134(20000515)39:3<197::aid-prot10>3.0.co;2-v.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Algorithms
  • Amino Acid Sequence
  • Animals
  • Apoptosis*
  • Apoptotic Protease-Activating Factor 1
  • Caenorhabditis elegans / chemistry
  • Caenorhabditis elegans Proteins*
  • Calcium-Binding Proteins / chemistry*
  • Calcium-Binding Proteins / metabolism*
  • Helminth Proteins / chemistry*
  • Helminth Proteins / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Protein Folding*
  • Protein Structure, Tertiary
  • Proteins / chemistry
  • Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship

Substances

  • APAF1 protein, human
  • Apoptotic Protease-Activating Factor 1
  • Caenorhabditis elegans Proteins
  • Calcium-Binding Proteins
  • Ced-4 protein, C elegans
  • Helminth Proteins
  • Peptide Fragments
  • Proteins
  • Adenosine Triphosphate