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Apoptosis PDB id
1ty4
Jmol
Contents
Protein chains
164 a.a. *
29 a.a. *
27 a.a. *
Waters ×67
* Residue conservation analysis
PDB id:
1ty4
Name: Apoptosis
Title: Crystal structure of a ced-9/egl-1 complex
Structure: Apoptosis regulator ced-9. Chain: a, b. Fragment: bh1,bh2. Synonym: cell death protein 9. Engineered: yes. Egg laying defective egl-1, programmed cell death activator. Chain: c, d. Engineered: yes
Source: Caenorhabditis elegans. Organism_taxid: 6239. Gene: ced-9,t07c4.8. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.20Å     R-factor:   0.212     R-free:   0.235
Authors: N.Yan,L.Gu,D.Kokel,D.Xue,Y.Shi
Key ref:
N.Yan et al. (2004). Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol Cell, 15, 999. PubMed id: 15383288 DOI: 10.1016/j.molcel.2004.08.022
Date:
07-Jul-04     Release date:   28-Sep-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P41958  (CED9_CAEEL) -  Apoptosis regulator ced-9
Seq:
Struc: 		280 a.a.
164 a.a.*
Protein chain
Pfam   ArchSchema ?
O61667  (EGL1_CAEEL) -  Programmed cell death activator egl-1
Seq:
Struc: 		106 a.a.
29 a.a.
Protein chain
Pfam   ArchSchema ?
O61667  (EGL1_CAEEL) -  Programmed cell death activator egl-1
Seq:
Struc: 		106 a.a.
27 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     regulation of apoptosis   1 term 

 

 
DOI no: 10.1016/j.molcel.2004.08.022 Mol Cell 15:999 (2004)
PubMed id: 15383288  
 
 
Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4.
N.Yan, L.Gu, D.Kokel, J.Chai, W.Li, A.Han, L.Chen, D.Xue, Y.Shi.
 
  ABSTRACT  
 
Programmed cell death in Caenorhabditis elegans is initiated by the binding of EGL-1 to CED-9, which disrupts the CED-4/CED-9 complex and allows CED-4 to activate the cell-killing caspase CED-3. Here we demonstrate that the C-terminal half of EGL-1 is necessary and sufficient for binding to CED-9 and for killing cells. Structure of the EGL-1/CED-9 complex revealed that EGL-1 adopts an extended alpha-helical conformation and induces substantial structural rearrangements in CED-9 upon binding. EGL-1 interface mutants failed to bind to CED-9 or to release CED-4 from the CED-4/CED-9 complex, and were unable to induce cell death in vivo. A surface patch on CED-9, different from that required for binding to EGL-1, was identified to be responsible for binding to CED-4. These data suggest a working mechanism for the release of CED-4 from the CED-4/CED-9 complex upon EGL-1 binding and provide a mechanistic framework for understanding apoptosis activation in C. elegans.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. EGL-1 Binding Induces Significant Structural Rearrangements in CED-9(A) A surface representation of the EGL-1-bound CED-9 and the free CED-9 (inset). These two CED-9 molecules are in the same orientation and can be superimposed with each other with 1.23 Šroot-mean-square deviation (rmsd). Note the absence of a hydrophobic surface cleft in the free CED-9.(B) Structural comparison of the EGL-1-bound CED-9 (cyan) and the free CED-9 (gray). For clarity, only regions of CED-9 surrounding the bound EGL-1 fragment are shown. Helix α4 and the following loop undergo drastic rearrangements upon binding to EGL-1. 		Figure 3.
Figure 3. Biochemical and Functional Analyses of the EGL-1/CED-9 and CED-4/CED-9 Interactions(A) A close-up view of the EGL-1/CED-9 interface. To better visualize the crowded interface, it is opened up to show its two components. The backbones of CED-9 and EGL-1 are shown in blue and pink, respectively, while their side chains are colored yellow and green, respectively. Hydrogen bonds are represented by red dashed lines.(B) Sequence alignment of EGL-1 from two related nematode species, C. elegans and C. briggsae. The conserved residues are highlighted in red and shown between the two EGL-1 sequences. Residues involved in intermolecular van der Waals contacts and hydrogen bonds are indicated by blue square and red arrows, respectively.(C) Biochemical analyses of the EGL-1/CED-9 interface. Mutant GST-EGL-1 fragments were immobilized on glutathione resin, and the WT CED-9 protein (Input, lane 1) was allowed to flow through the resin. After washing, what remained on the resin was visualized on SDS-PAGE followed by Coomassie staining. The two mutants, mut2 and mut4, represent G55E/F65A and G55E/L58A/F65A/M69A, respectively.(D) The strength of EGL-1 binding to CED-9 directly correlates with the ability of EGL-1 to displace CED-4 from the CED-4/CED-9 complex.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2004, 15, 999-0) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21245325 B.D.Galvin, D.P.Denning, and H.R.Horvitz (2011).
SPK-1, an SR protein kinase, inhibits programmed cell death in Caenorhabditis elegans.
  Proc Natl Acad Sci U S A, 108, 1998-2003.  
21444803 E.F.Lee, O.B.Clarke, M.Evangelista, Z.Feng, T.P.Speed, E.B.Tchoubrieva, A.Strasser, B.H.Kalinna, P.M.Colman, and W.D.Fairlie (2011).
Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes.
  Proc Natl Acad Sci U S A, 108, 6999-7003.
PDB code: 3qbr
20817427 P.D.Mace, and S.J.Riedl (2010).
Molecular cell death platforms and assemblies.
  Curr Opin Cell Biol, 22, 828-836.  
19855391 M.Dreze, B.Charloteaux, S.Milstein, P.O.Vidalain, M.A.Yildirim, Q.Zhong, N.Svrzikapa, V.Romero, G.Laloux, R.Brasseur, J.Vandenhaute, M.Boxem, M.E.Cusick, D.E.Hill, and M.Vidal (2009).
'Edgetic' perturbation of a C. elegans BCL2 ortholog.
  Nat Methods, 6, 843-849.  
19414600 Q.Shen, F.Qin, Z.Gao, J.Cui, H.Xiao, Z.Xu, and C.Yang (2009).
Adenine nucleotide translocator cooperates with core cell death machinery to promote apoptosis in Caenorhabditis elegans.
  Mol Cell Biol, 29, 3881-3893.  
  19704021 S.G.Rolland, Y.Lu, C.N.David, and B.Conradt (2009).
The BCL-2-like protein CED-9 of C. elegans promotes FZO-1/Mfn1,2- and EAT-3/Opa1-dependent mitochondrial fusion.
  J Cell Biol, 186, 525-540.  
19767395 Z.Mei, F.Wang, Y.Qi, Z.Zhou, Q.Hu, H.Li, J.Wu, and Y.Shi (2009).
Molecular determinants of MecA as a degradation tag for the ClpCP protease.
  J Biol Chem, 284, 34366-34375.  
18452209 D.Lama, and R.Sankararamakrishnan (2008).
Anti-apoptotic Bcl-XL protein in complex with BH3 peptides of pro-apoptotic Bak, Bad, and Bim proteins: comparative molecular dynamics simulations.
  Proteins, 73, 492-514.  
18566606 E.F.Lee, L.Chen, H.Yang, P.M.Colman, D.C.Huang, and W.D.Fairlie (2008).
EGL-1 BH3 mutants reveal the importance of protein levels and target affinity for cell-killing potency.
  Cell Death Differ, 15, 1609-1618.  
19641503 E.Lomonosova, and G.Chinnadurai (2008).
BH3-only proteins in apoptosis and beyond: an overview.
  Oncogene, 27, S2-19.  
  18719375 E.Peden, D.J.Killian, and D.Xue (2008).
Cell death specification in C. elegans.
  Cell Cycle, 7, 2479-2484.  
18437162 E.S.Blum, M.Driscoll, and S.Shaham (2008).
Noncanonical cell death programs in the nematode Caenorhabditis elegans.
  Cell Death Differ, 15, 1124-1131.  
18827010 F.J.Tan, M.Husain, C.M.Manlandro, M.Koppenol, A.Z.Fire, and R.B.Hill (2008).
CED-9 and mitochondrial homeostasis in C. elegans muscle.
  J Cell Sci, 121, 3373-3382.  
19641505 R.Nehme, and B.Conradt (2008).
egl-1: a key activator of apoptotic cell death in C. elegans.
  Oncogene, 27, S30-S40.  
18923081 S.Greiss, J.Hall, S.Ahmed, and A.Gartner (2008).
C. elegans SIR-2.1 translocation is linked to a proapoptotic pathway parallel to cep-1/p53 during DNA damage-induced apoptosis.
  Genes Dev, 22, 2831-2842.  
18832646 X.Deng, X.Yin, R.Allan, D.D.Lu, C.W.Maurer, A.Haimovitz-Friedman, Z.Fuks, S.Shaham, and R.Kolesnick (2008).
Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans.
  Science, 322, 110-115.  
17391014 H.Xie, S.Vucetic, L.M.Iakoucheva, C.J.Oldfield, A.K.Dunker, V.N.Uversky, and Z.Obradovic (2007).
Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions.
  J Proteome Res, 6, 1882-1898.  
17347667 L.Stergiou, K.Doukoumetzidis, A.Sendoel, and M.O.Hengartner (2007).
The nucleotide excision repair pathway is required for UV-C-induced apoptosis in Caenorhabditis elegans.
  Cell Death Differ, 14, 1129-1138.  
16645638 M.G.Hinds, C.Smits, R.Fredericks-Short, J.M.Risk, M.Bailey, D.C.Huang, and C.L.Day (2007).
Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets.
  Cell Death Differ, 14, 128-136.  
16691212 A.Manoharan, T.Kiefer, S.Leist, K.Schrader, C.Urban, D.Walter, U.Maurer, and C.Borner (2006).
Identification of a 'genuine' mammalian homolog of nematodal CED-4: is the hunt over or do we need better guns?
  Cell Death Differ, 13, 1310-1317.  
16842034 B.A.Hay, and M.Guo (2006).
Caspase-dependent cell death in Drosophila.
  Annu Rev Cell Dev Biol, 22, 623-650.  
16467303 C.Yang, N.Yan, J.Parish, X.Wang, Y.Shi, and D.Xue (2006).
RNA aptamers targeting the cell death inhibitor CED-9 induce cell killing in Caenorhabditis elegans.
  J Biol Chem, 281, 9137-9144.  
16699520 D.Kokel, Y.Li, J.Qin, and D.Xue (2006).
The nongenotoxic carcinogens naphthalene and para-dichlorobenzene suppress apoptosis in Caenorhabditis elegans.
  Nat Chem Biol, 2, 338-345.  
16912277 E.A.Kritikou, S.Milstein, P.O.Vidalain, G.Lettre, E.Bogan, K.Doukoumetzidis, P.Gray, T.G.Chappell, M.Vidal, and M.O.Hengartner (2006).
C. elegans GLA-3 is a novel component of the MAP kinase MPK-1 signaling pathway required for germ cell survival.
  Genes Dev, 20, 2279-2292.  
16493416 G.Lettre, and M.O.Hengartner (2006).
Developmental apoptosis in C. elegans: a complex CEDnario.
  Nat Rev Mol Cell Biol, 7, 97.  
17005564 J.Peng, C.Tan, G.J.Roberts, O.Nikolaeva, Z.Zhang, S.M.Lapolla, S.Primorac, D.W.Andrews, and J.Lin (2006).
tBid elicits a conformational alteration in membrane-bound Bcl-2 such that it inhibits Bax pore formation.
  J Biol Chem, 281, 35802-35811.  
16770683 S.R.Dunn, W.S.Phillips, J.W.Spatafora, D.R.Green, and V.M.Weis (2006).
Highly conserved caspase and Bcl-2 homologues from the sea anemone Aiptasia pallida: lower metazoans as models for the study of apoptosis evolution.
  J Mol Evol, 63, 95.  
16167070 W.D.Fairlie, M.A.Perugini, M.Kvansakul, L.Chen, D.C.Huang, and P.M.Colman (2006).
CED-4 forms a 2 : 2 heterotetrameric complex with CED-9 until specifically displaced by EGL-1 or CED-13.
  Cell Death Differ, 13, 426-434.  
17046227 Y.Shi (2006).
Mechanical aspects of apoptosome assembly.
  Curr Opin Cell Biol, 18, 677-684.  
15550399 C.L.Day, L.Chen, S.J.Richardson, P.J.Harrison, D.C.Huang, and M.G.Hinds (2005).
Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands.
  J Biol Chem, 280, 4738-4744.
PDB code: 1wsx
16208361 N.Yan, J.Chai, E.S.Lee, L.Gu, Q.Liu, J.He, J.W.Wu, D.Kokel, H.Li, Q.Hao, D.Xue, and Y.Shi (2005).
Structure of the CED-4-CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans.
  Nature, 437, 831-837.
PDB code: 2a5y
16212486 N.Yan, and Y.Shi (2005).
Mechanisms of apoptosis through structural biology.
  Annu Rev Cell Dev Biol, 21, 35-56.  
16243507 S.N.Willis, and J.M.Adams (2005).
Life in the balance: how BH3-only proteins induce apoptosis.
  Curr Opin Cell Biol, 17, 617-625.  
15573123 B.A.Hay, J.R.Huh, and M.Guo (2004).
The genetics of cell death: approaches, insights and opportunities in Drosophila.
  Nat Rev Genet, 5, 911-922.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.