8jns

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cryo-EM structure of a CED-4 hexamercryo-EM structure of a CED-4 hexamer

Structural highlights

8jns is a 9 chain structure with sequence from Caenorhabditis elegans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 4.2Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CED4_CAEEL Isoform a plays a major role in programmed cell death (PCD, apoptosis). Egl-1 binds to and directly inhibits the activity of ced-9, releasing the cell death activator ced-4 from a ced-9/ced-4 containing protein complex and allowing ced-4 to activate the cell-killing caspase ced-3. Isoform b prevents PCD.[1] [2] [3] [4] [5]

Publication Abstract from PubMed

In Caenorhabditis elegans (C. elegans), onset of programmed cell death is marked with the activation of CED-3, a process that requires assembly of the CED-4 apoptosome. Activated CED-3 forms a holoenzyme with the CED-4 apoptosome to cleave a wide range of substrates, leading to irreversible cell death. Despite decades of investigations, the underlying mechanism of CED-4-facilitated CED-3 activation remains elusive. Here, we report cryo-EM structures of the CED-4 apoptosome and three distinct CED-4/CED-3 complexes that mimic different activation stages for CED-3. In addition to the previously reported octamer in crystal structures, CED-4, alone or in complex with CED-3, exists in multiple oligomeric states. Supported by biochemical analyses, we show that the conserved CARD-CARD interaction promotes CED-3 activation, and initiation of programmed cell death is regulated by the dynamic organization of the CED-4 apoptosome.

Structural insights into CED-3 activation.,Li Y, Tian L, Zhang Y, Shi Y Life Sci Alliance. 2023 Jul 4;6(9):e202302056. doi: 10.26508/lsa.202302056. Print , 2023 Sep. PMID:37402593[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Yuan J, Horvitz HR. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development. 1992 Oct;116(2):309-20. PMID:1286611
  2. ↑ Shaham S, Horvitz HR. An alternatively spliced C. elegans ced-4 RNA encodes a novel cell death inhibitor. Cell. 1996 Jul 26;86(2):201-8. PMID:8706125
  3. ↑ Wu D, Wallen HD, Nunez G. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science. 1997 Feb 21;275(5303):1126-9. PMID:9027313
  4. ↑ Chen F, Hersh BM, Conradt B, Zhou Z, Riemer D, Gruenbaum Y, Horvitz HR. Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science. 2000 Feb 25;287(5457):1485-9. PMID:10688797
  5. ↑ Yan N, Gu L, Kokel D, Chai J, Li W, Han A, Chen L, Xue D, Shi Y. Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol Cell. 2004 Sep 24;15(6):999-1006. PMID:15383288 doi:10.1016/j.molcel.2004.08.022
  6. ↑ Li Y, Tian L, Zhang Y, Shi Y. Structural insights into CED-3 activation. Life Sci Alliance. 2023 Jul 4;6(9):e202302056. PMID:37402593 doi:10.26508/lsa.202302056

8jns, resolution 4.20Å

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