Chinnaiyan AM et al. (1997) Science "Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death."

Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM

[Science, 1997]

Previous genetic studies of the nematode Caenorhabditis elegans identified three important components of the cell death machinery. CED-3 and CED-4 function to kill cells, whereas CED-9 protects cells from death. Here CED-9 and its mammalian homolog Bcl-xL (a member of the Bcl-2 family of cell death regulators) were both found to interact with and inhibit the function of CED-4. In addition, analysis revealed that CED-4 can simultaneously interact with CED-3 and its mammalian counterparts interleukin-1beta-converting enzyme (ICE) and FLICE. Thus, CED-4 plays a central role in the cell death pathway, biochemically linking CED-9 and the Bcl-2 family to CED-3 and the ICE family of pro-apoptotic cysteine proteases.AD - University of Michigan Medical School, Department of Pathology, Ann Arbor, MI 48109, USA.FAU - Chinnaiyan, A MAU - Chinnaiyan AMFAU - O'Rourke, KAU - O'Rourke KFAU - Lane, B RAU - Lane BRFAU - Dixit, V MAU - Dixit VMLA - engID - 7863/PHSPT - Journal ArticleCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Calcium-Binding Proteins)RN - 0 (Ced-4 protein)RN - 0 (Ced-9 protein)RN - 0 (Helminth Proteins)RN - 0 (Proto-Oncogene Proteins)RN - 0 (bcl-x protein)RN - EC 3.4.22 (Cysteine Endopeptidases)RN - EC 3.4.22.- (Ced-3 protein)RN - EC 3.4.22.- (caspase 8)RN - EC 3.4.22.36 (Caspase 1)SB - IM

Jaroszewski L et al. (2000) Proteins "ATP-activated oligomerization as a mechanism for apoptosis regulation: fold and mechanism prediction for CED-4."

Reed JC, Rychlewski L, Godzik A, Jaroszewski L

[Proteins, 2000]

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.