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PDBsum entry 1q4q
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Apoptosis inhibitor PDB id
1q4q

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
(+ 0 more) 94 a.a. *
101 a.a. *
Ligands
ARG-PRO-PRO-PHE-
ILE-SER-LEU-ASN ×5
PRO-PRO-PHE-ILE-
SER-LEU-ASN ×5
Metals
_ZN ×10
Waters ×557
* Residue conservation analysis
PDB id:
1q4q
Name: Apoptosis inhibitor
Title: Crystal structure of a diap1-dronc complex
Structure: Apoptosis 1 inhibitor. Chain: a, b, c, d, e, f, g, h, i, j. Fragment: diap1 bir2 domain, residues 201-324. Synonym: inhibitor of apoptosis 1, diap1, thread protein. Engineered: yes. Nedd2-like caspase cg8091-pa. Chain: k, l, m, n, o, p, q, r, s, t. Fragment: dronc peptide, residues 114-125. Synonym: dronc.
Source: Drosophila melanogaster. Fruit fly. Organism_taxid: 7227. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the peptide was synthesized.
Biol. unit: Not given
Resolution:
2.10Å     R-factor:   0.199     R-free:   0.246
Authors: J.Chai,N.Yan,Y.Shi
Key ref:
J.Chai et al. (2003). Molecular mechanism of Reaper-Grim-Hid-mediated suppression of DIAP1-dependent Dronc ubiquitination. Nat Struct Biol, 10, 892-898. PubMed id: 14517550 DOI: 10.1038/nsb989
Date:
04-Aug-03     Release date:   04-Nov-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q24306  (DIAP1_DROME) -  Death-associated inhibitor of apoptosis 1 from Drosophila melanogaster
Seq:
Struc: 		438 a.a.
94 a.a.
Protein chains
Pfam   ArchSchema ?
Q24306  (DIAP1_DROME) -  Death-associated inhibitor of apoptosis 1 from Drosophila melanogaster
Seq:
Struc: 		438 a.a.
101 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D, E, F, G, H, I, J: E.C.2.3.2.27  - RING-type E3 ubiquitin transferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6- ubiquitinyl-[acceptor protein]-L-lysine

 

 
DOI no: 10.1038/nsb989 Nat Struct Biol 10:892-898 (2003)
PubMed id: 14517550  
 
 
Molecular mechanism of Reaper-Grim-Hid-mediated suppression of DIAP1-dependent Dronc ubiquitination.
J.Chai, N.Yan, J.R.Huh, J.W.Wu, W.Li, B.A.Hay, Y.Shi.
 
  ABSTRACT  
 
The inhibitor of apoptosis protein DIAP1 inhibits Dronc-dependent cell death by ubiquitinating Dronc. The pro-death proteins Reaper, Hid and Grim (RHG) promote apoptosis by antagonizing DIAP1 function. Here we report the structural basis of Dronc recognition by DIAP1 as well as a novel mechanism by which the RHG proteins remove DIAP1-mediated downregulation of Dronc. Biochemical and structural analyses revealed that the second BIR (BIR2) domain of DIAP1 recognizes a 12-residue sequence in Dronc. This recognition is essential for DIAP1 binding to Dronc, and for targeting Dronc for ubiquitination. Notably, the Dronc-binding surface on BIR2 coincides with that required for binding to the N termini of the RHG proteins, which competitively eliminate DIAP1-mediated ubiquitination of Dronc. These observations reveal the molecular mechanisms of how DIAP1 recognizes Dronc, and more importantly, how the RHG proteins remove DIAP1-mediated ubiquitination of Dronc.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. Dronc and Hid compete with each other for binding to the same surface groove on the BIR2 domain of DIAP1. (a) Stereo superposition of the structures of DIAP1-BIR2 bound to Dronc and to Hid peptide. The Dronc and Hid peptides are green and orange, respectively. Note the difference in the orientation of the two peptides. Phe118 of Dronc and Phe4 of Hid occupy the same general pocket on the surface of DIAP1. (b) A ten-residue peptide derived from the N terminus of Hid disrupts the interaction between Dronc and DIAP1. GST-BIR2-Dronc (1 -136) complex (1.2 mg) was used for each gel filtration run. Hid peptide (60 g) was used to disrupt the BIR2 -Dronc complex. The chromatograms for gel filtration are on the left and the relevant fractions from gel filtration were visualized by SDS-PAGE and stained with Coomassie blue. 		Figure 5.
Figure 5. Molecular mechanism of the removal of DIAP1-mediated Dronc ubiquitination by the pro-apoptosis protein Hid. (a) The BIR2 domain is required for the ubiquitination of Dronc in vitro. Various DIAP1 fragments were examined for their E3 ubiquitin ligase activity in the ubiquitination reaction of Dronc (C318A). The gel was blotted using an anti-Dronc raised against its CARD domain. E1, E2, Dronc (C318A) and DIAP1 were individually purified to homogeneity as described in Methods. (b) A ten-residue peptide derived from the N terminus of Hid specifically removes DIAP1-mediated ubiquitination of Dronc. The control peptide has the sequence N-DYPDQNRRRIGAEK-C.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 892-898) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21113144 A.Khammari, F.Agnès, P.Gandille, and A.M.Pret (2011).
Physiological apoptosis of polar cells during Drosophila oogenesis is mediated by Hid-dependent regulation of Diap1.
  Cell Death Differ, 18, 793-805.  
21274634 H.Wang, and R.J.Clem (2011).
The role of IAP antagonist proteins in the core apoptosis pathway of the mosquito disease vector Aedes aegypti.
  Apoptosis, 16, 235-248.  
21220123 S.Yuan, X.Yu, M.Topf, L.Dorstyn, S.Kumar, S.J.Ludtke, and C.W.Akey (2011).
Structure of the Drosophila apoptosome at 6.9 å resolution.
  Structure, 19, 128-140.
PDB codes: 1vt4 3iz8
19498442 A.Bergmann (2010).
The role of ubiquitylation for the control of cell death in Drosophila.
  Cell Death Differ, 17, 61-67.  
20837774 C.Sandu, H.D.Ryoo, and H.Steller (2010).
Drosophila IAP antagonists form multimeric complexes to promote cell death.
  J Cell Biol, 190, 1039-1052.  
21145488 M.Broemer, T.Tenev, K.T.Rigbolt, S.Hempel, B.Blagoev, J.Silke, M.Ditzel, and P.Meier (2010).
Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases.
  Mol Cell, 40, 810-822.  
20651737 M.Gyrd-Hansen, and P.Meier (2010).
IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer.
  Nat Rev Cancer, 10, 561-574.  
19523066 B.Bryant, Y.Zhang, C.Zhang, C.P.Santos, R.J.Clem, and L.Zhou (2009).
A lepidopteran orthologue of reaper reveals functional conservation and evolution of IAP antagonists.
  Insect Mol Biol, 18, 341-351.  
19659442 C.Wang, and R.J.Youle (2009).
The role of mitochondria in apoptosis*.
  Annu Rev Genet, 43, 95.  
19212814 D.M.Cooper, D.J.Granville, and C.Lowenberger (2009).
The insect caspases.
  Apoptosis, 14, 247-256.  
  19182545 D.Xu, S.E.Woodfield, T.V.Lee, Y.Fan, C.Antonio, and A.Bergmann (2009).
Genetic control of programmed cell death (apoptosis) in Drosophila.
  Fly (Austin), 3, 78-90.  
19428445 M.A.Bedoukian, S.M.Rodriguez, M.B.Cohen, S.V.Duncan Smith, and J.Park (2009).
Neuronal susceptibility to GRIM in Drosophila melanogaster measures the rate of genetic changes that scale to lifespan.
  Mech Ageing Dev, 130, 281-289.  
19850458 M.Bader, and H.Steller (2009).
Regulation of cell death by the ubiquitin-proteasome system.
  Curr Opin Cell Biol, 21, 878-884.  
19217783 M.Broemer, and P.Meier (2009).
Ubiquitin-mediated regulation of apoptosis.
  Trends Cell Biol, 19, 130-140.  
19737742 M.Mallik, and S.C.Lakhotia (2009).
The developmentally active and stress-inducible noncoding hsromega gene is a novel regulator of apoptosis in Drosophila.
  Genetics, 183, 831-852.  
19495985 M.Orme, and P.Meier (2009).
Inhibitor of apoptosis proteins in Drosophila: gatekeepers of death.
  Apoptosis, 14, 950-960.  
19100727 M.Tanaka-Matakatsu, J.Xu, L.Cheng, and W.Du (2009).
Regulation of apoptosis of rbf mutant cells during Drosophila development.
  Dev Biol, 326, 347-356.  
19258326 Y.E.Choi, M.Butterworth, S.Malladi, C.S.Duckett, G.M.Cohen, and S.B.Bratton (2009).
The E3 Ubiquitin Ligase cIAP1 Binds and Ubiquitinates Caspase-3 and -7 via Unique Mechanisms at Distinct Steps in Their Processing.
  J Biol Chem, 284, 12772-12782.  
18252247 B.Bryant, C.D.Blair, K.E.Olson, and R.J.Clem (2008).
Annotation and expression profiling of apoptosis-related genes in the yellow fever mosquito, Aedes aegypti.
  Insect Biochem Mol Biol, 38, 331-345.  
17989181 E.W.Settles, and P.D.Friesen (2008).
Flock house virus induces apoptosis by depletion of Drosophila inhibitor-of-apoptosis protein DIAP1.
  J Virol, 82, 1378-1388.  
18259196 F.S.Khan, M.Fujioka, P.Datta, T.Fernandes-Alnemri, J.B.Jaynes, and E.S.Alnemri (2008).
The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila.
  Cell Death Differ, 15, 1073-1083.  
19026784 M.Ditzel, M.Broemer, T.Tenev, C.Bolduc, T.V.Lee, K.T.Rigbolt, R.Elliott, M.Zvelebil, B.Blagoev, A.Bergmann, and P.Meier (2008).
Inactivation of effector caspases through nondegradative polyubiquitylation.
  Mol Cell, 32, 540-553.  
18854135 M.X.O'Riordan, L.D.Bauler, F.L.Scott, and C.S.Duckett (2008).
Inhibitor of apoptosis proteins in eukaryotic evolution and development: a model of thematic conservation.
  Dev Cell, 15, 497-508.  
18045837 T.V.Lee, T.Ding, Z.Chen, V.Rajendran, H.Scherr, M.Lackey, C.Bolduc, and A.Bergmann (2008).
The E1 ubiquitin-activating enzyme Uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously.
  Development, 135, 43-52.  
17094177 A.Kurakin, and D.E.Bredesen (2007).
An unconventional IAP-binding motif revealed by target-assisted iterative screening (TAIS) of the BIR3-cIAP1 domain.
  J Mol Recognit, 20, 39-50.  
17998402 C.H.Yi, D.K.Sogah, M.Boyce, A.Degterev, D.E.Christofferson, and J.Yuan (2007).
A genome-wide RNAi screen reveals multiple regulators of caspase activation.
  J Cell Biol, 179, 619-626.  
17582002 E.Lannan, R.Vandergaast, and P.D.Friesen (2007).
Baculovirus caspase inhibitors P49 and P35 block virus-induced apoptosis downstream of effector caspase DrICE activation in Drosophila melanogaster cells.
  J Virol, 81, 9319-9330.  
17612403 J.M.Copeland, I.Bosdet, J.D.Freeman, M.Guo, S.M.Gorski, and B.A.Hay (2007).
echinus, required for interommatidial cell sorting and cell death in the Drosophila pupal retina, encodes a protein with homology to ubiquitin-specific proteases.
  BMC Dev Biol, 7, 82.  
17068333 J.R.Huh, I.Foe, I.Muro, C.H.Chen, J.H.Seol, S.J.Yoo, M.Guo, J.M.Park, and B.A.Hay (2007).
The Drosophila inhibitor of apoptosis (IAP) DIAP2 is dispensable for cell survival, required for the innate immune response to gram-negative bacterial infection, and can be negatively regulated by the reaper/hid/grim family of IAP-binding apoptosis inducers.
  J Biol Chem, 282, 2056-2068.  
17557079 M.Challa, S.Malladi, B.J.Pellock, D.Dresnek, S.Varadarajan, Y.W.Yin, K.White, and S.B.Bratton (2007).
Drosophila Omi, a mitochondrial-localized IAP antagonist and proapoptotic serine protease.
  EMBO J, 26, 3144-3156.  
17205079 Y.Herman-Bachinsky, H.D.Ryoo, A.Ciechanover, and H.Gonen (2007).
Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways.
  Cell Death Differ, 14, 861-871.  
16842034 B.A.Hay, and M.Guo (2006).
Caspase-dependent cell death in Drosophila.
  Annu Rev Cell Dev Biol, 22, 623-650.  
16322754 J.C.Means, I.Muro, and R.J.Clem (2006).
Lack of involvement of mitochondrial factors in caspase activation in a Drosophila cell-free system.
  Cell Death Differ, 13, 1222-1234.  
16710365 M.Thomenius, and S.Kornbluth (2006).
Multifunctional reaper: sixty-five amino acids of fury.
  Cell Death Differ, 13, 1305-1309.  
15803136 D.L.Vaux, and J.Silke (2005).
IAPs, RINGs and ubiquitylation.
  Nat Rev Mol Cell Biol, 6, 287-297.  
16094398 D.L.Vaux, and J.Silke (2005).
IAPs--the ubiquitin connection.
  Cell Death Differ, 12, 1205-1207.  
15800001 D.Xu, Y.Li, M.Arcaro, M.Lackey, and A.Bergmann (2005).
The CARD-carrying caspase Dronc is essential for most, but not all, developmental cell death in Drosophila.
  Development, 132, 2125-2134.  
15650747 F.L.Scott, J.B.Denault, S.J.Riedl, H.Shin, M.Renatus, and G.S.Salvesen (2005).
XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs.
  EMBO J, 24, 645-655.  
15774476 I.Muro, J.C.Means, and R.J.Clem (2005).
Cleavage of the apoptosis inhibitor DIAP1 by the apical caspase DRONC in both normal and apoptotic Drosophila cells.
  J Biol Chem, 280, 18683-18688.  
16094399 M.Ditzel, and P.Meier (2005).
Ubiquitylation in apoptosis: DIAP1's (N-)en(d)igma.
  Cell Death Differ, 12, 1208-1212.  
16212486 N.Yan, and Y.Shi (2005).
Mechanisms of apoptosis through structural biology.
  Annu Rev Cell Dev Biol, 21, 35-56.  
15797833 P.Cashio, T.V.Lee, and A.Bergmann (2005).
Genetic control of programmed cell death in Drosophila melanogaster.
  Semin Cell Dev Biol, 16, 225-235.  
15681434 Q.Li, P.Liston, and R.W.Moyer (2005).
Functional analysis of the inhibitor of apoptosis (iap) gene carried by the entomopoxvirus of Amsacta moorei.
  J Virol, 79, 2335-2345.  
15114336 B.A.Schreader, and J.R.Nambu (2004).
A fine balance for life and death decisions.
  Nat Struct Mol Biol, 11, 386-388.  
14737191 J.R.Huh, S.Y.Vernooy, H.Yu, N.Yan, Y.Shi, M.Guo, and B.A.Hay (2004).
Multiple apoptotic caspase cascades are required in nonapoptotic roles for Drosophila spermatid individualization.
  PLoS Biol, 2, E15.  
15107838 N.Yan, J.W.Wu, J.Chai, W.Li, and Y.Shi (2004).
Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim.
  Nat Struct Mol Biol, 11, 420-428.
PDB codes: 1sdz 1se0
15520809 S.J.Riedl, and Y.Shi (2004).
Molecular mechanisms of caspase regulation during apoptosis.
  Nat Rev Mol Cell Biol, 5, 897-907.  
15371434 T.Yokokura, D.Dresnek, N.Huseinovic, S.Lisi, E.Abdelwahid, P.Bangs, and K.White (2004).
Dissection of DIAP1 functional domains via a mutant replacement strategy.
  J Biol Chem, 279, 52603-52612.  
15273300 Y.Shi (2004).
Caspase activation, inhibition, and reactivation: a mechanistic view.
  Protein Sci, 13, 1979-1987.  
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 codes are shown on the right.

 

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