PDBsum entry 1e41

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Apoptosis PDB id
Protein chain
104 a.a. *
* Residue conservation analysis
PDB id:
Name: Apoptosis
Title: Death domain from human fadd/mort1
Structure: Fadd protein. Chain: a. Fragment: death domain residues 93-192. Synonym: fas-associating death domain-containing protein. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Other_details: pcr cloning into n-terminal 6 His tag thrombin-cleavable fusion protein
NMR struc: 25 models
Authors: P.C.Driscoll,H.Berglund,D.Olerenshaw,N.Q.Mcdonald
Key ref:
H.Berglund et al. (2000). The three-dimensional solution structure and dynamic properties of the human FADD death domain. J Mol Biol, 302, 171-188. PubMed id: 10964568 DOI: 10.1006/jmbi.2000.4011
27-Jun-00     Release date:   06-Nov-00    
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Protein chain
Pfam   ArchSchema ?
Q13158  (FADD_HUMAN) -  FAS-associated death domain protein
208 a.a.
104 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     signal transduction   1 term 


DOI no: 10.1006/jmbi.2000.4011 J Mol Biol 302:171-188 (2000)
PubMed id: 10964568  
The three-dimensional solution structure and dynamic properties of the human FADD death domain.
H.Berglund, D.Olerenshaw, A.Sankar, M.Federwisch, N.Q.McDonald, P.C.Driscoll.
FADD (also known as MORT-1) is an essential adapter protein that couples the transmembrane receptors Fas (CD95) and tumor necrosis factor receptor-1 (TNF-R1) to intracellular cysteine proteases known as caspases, which propagate and execute the programmed cell death-inducing signal triggered by Fas ligand (FasL, CD95L) and TNF. FADD contains 208 amino acid residues, and comprises two functionally and structurally distinct domains: an N-terminal death effector domain (DED) that promotes activation of the downstream proteolytic cascade through binding of the DED domains of procaspase-8; and a C-terminal death domain (DD). FADD-DD provides the site of FADD recruitment to death receptor complexes at the plasma membrane by, for example, interaction with the Fas receptor cytoplasmic death domain (Fas-DD), or binding of the TNF-R1 adapter molecule TRADD. We have determined the three-dimensional solution structure and characterised the internal polypeptide dynamics of human FADD-DD using heteronuclear NMR spectroscopy of (15)N and (13)C,(15)N-labelled samples. The structure comprises six alpha-helices joined by short loops and displays overall similarity to the death domain of the Fas receptor. The analysis of the dynamic properties reveals no evidence of contiguous stretches of polypeptide chain with increased internal motion, except at the extreme chain termini. A pattern of increased rates of amide proton solvent exchange in the alpha3 helix correlates with a higher degree of solvent exposure for this secondary structure element. The properties of the FADD-DD structure are discussed with respect to previously reported mutagenesis data and emerging models for FasL-induced FADD recruitment to Fas and caspase-8 activation.
  Selected figure(s)  
Figure 4.
Figure 4. Schematic ribbons-style drawing of the restrained minimised average structure of human (a) FADD-DD and (b) Fas-DD (PDB code 1DDF). The side-chain of the lpr mutation site (V238) in Fas-DD, and the corresponding residue (V121) in FADD-DD is shown. The Figure was produced with the program MOLSCRIPT [Kraulis 1991] and rendered with RASTER3D [Merritt and Murphy 1994].
Figure 7.
Figure 7. Solvent-accessible surface representations of the structures of (a) human FADD-DD and (b) Fas-DD coloured according to the electrostatic potential (positive potential blue, negative potential red). The charged side-chains are labelled in yellow, with those implicated by mutagenesis in Fas-FADD binding indicated by underlining. The orientation of the structure is approximately the reverse side of that shown in Figure 4. The Figure was created in MOLMOL [Koradi et al 1996].
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 302, 171-188) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21207148 H.H.Park (2011).
Structural analyses of death domains and their interactions.
  Apoptosis, 16, 209-220.  
20935634 L.Wang, J.K.Yang, V.Kabaleeswaran, A.J.Rice, A.C.Cruz, A.Y.Park, Q.Yin, E.Damko, S.B.Jang, S.Raunser, C.V.Robinson, R.M.Siegel, T.Walz, and H.Wu (2010).
The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations.
  Nat Struct Mol Biol, 17, 1324-1329.
PDB code: 3oq9
19362094 A.Steward, G.S.McDowell, and J.Clarke (2009).
Topology is the principal determinant in the folding of a complex all-alpha Greek key death domain from human FADD.
  J Mol Biol, 389, 425-437.  
19118384 F.L.Scott, B.Stec, C.Pop, M.K.Dobaczewska, J.J.Lee, E.Monosov, H.Robinson, G.S.Salvesen, R.Schwarzenbacher, and S.J.Riedl (2009).
The Fas-FADD death domain complex structure unravels signalling by receptor clustering.
  Nature, 457, 1019-1022.
PDB code: 3ezq
19203997 H.Z.Imtiyaz, X.Zhou, H.Zhang, D.Chen, T.Hu, and J.Zhang (2009).
The death domain of FADD is essential for embryogenesis, lymphocyte development, and proliferation.
  J Biol Chem, 284, 9917-9926.  
19679662 M.Loiarro, G.Gallo, N.Fantò, R.De Santis, P.Carminati, V.Ruggiero, and C.Sette (2009).
Identification of critical residues of the MyD88 death domain involved in the recruitment of downstream kinases.
  J Biol Chem, 284, 28093-28103.  
18931689 J.W.Yu, and Y.Shi (2008).
FLIP and the death effector domain family.
  Oncogene, 27, 6216-6227.  
17599096 B.J.Ferguson, D.Esposito, J.Jovanović, A.Sankar, P.C.Driscoll, and H.Mehmet (2007).
Biophysical and cell-based evidence for differential interactions between the death domains of CD95/Fas and FADD.
  Cell Death Differ, 14, 1717-1719.  
17201679 H.H.Park, Y.C.Lo, S.C.Lin, L.Wang, J.K.Yang, and H.Wu (2007).
The death domain superfamily in intracellular signaling of apoptosis and inflammation.
  Annu Rev Immunol, 25, 561-586.  
17943131 P.C.Sabeti, P.Varilly, B.Fry, J.Lohmueller, E.Hostetter, C.Cotsapas, X.Xie, E.H.Byrne, S.A.McCarroll, R.Gaudet, S.F.Schaffner, E.S.Lander, K.A.Frazer, D.G.Ballinger, D.R.Cox, D.A.Hinds, L.L.Stuve, R.A.Gibbs, J.W.Belmont, A.Boudreau, P.Hardenbol, S.M.Leal, S.Pasternak, D.A.Wheeler, T.D.Willis, F.Yu, H.Yang, C.Zeng, Y.Gao, H.Hu, W.Hu, C.Li, W.Lin, S.Liu, H.Pan, X.Tang, J.Wang, W.Wang, J.Yu, B.Zhang, Q.Zhang, H.Zhao, H.Zhao, J.Zhou, S.B.Gabriel, R.Barry, B.Blumenstiel, A.Camargo, M.Defelice, M.Faggart, M.Goyette, S.Gupta, J.Moore, H.Nguyen, R.C.Onofrio, M.Parkin, J.Roy, E.Stahl, E.Winchester, L.Ziaugra, D.Altshuler, Y.Shen, Z.Yao, W.Huang, X.Chu, Y.He, L.Jin, Y.Liu, Y.Shen, W.Sun, H.Wang, Y.Wang, Y.Wang, X.Xiong, L.Xu, M.M.Waye, S.K.Tsui, H.Xue, J.T.Wong, L.M.Galver, J.B.Fan, K.Gunderson, S.S.Murray, A.R.Oliphant, M.S.Chee, A.Montpetit, F.Chagnon, V.Ferretti, M.Leboeuf, J.F.Olivier, M.S.Phillips, S.Roumy, C.Sallée, A.Verner, T.J.Hudson, P.Y.Kwok, D.Cai, D.C.Koboldt, R.D.Miller, and L.Pawlikowska (2007).
Genome-wide detection and characterization of positive selection in human populations.
  Nature, 449, 913-918.  
16977332 Q.Bao, and Y.Shi (2007).
Apoptosome: a platform for the activation of initiator caspases.
  Cell Death Differ, 14, 56-65.  
17040621 A.D.Schimmer (2006).
Induction of apoptosis in lymphoid and myeloid leukemia.
  Curr Oncol Rep, 8, 430-436.  
16981827 A.E.McKee, and C.J.Thiele (2006).
Targeting caspase 8 to reduce the formation of metastases in neuroblastoma.
  Expert Opin Ther Targets, 10, 703-708.  
16710361 C.Sandu, G.Morisawa, I.Wegorzewska, T.Huang, A.F.Arechiga, J.M.Hill, T.Kim, C.M.Walsh, and M.H.Werner (2006).
FADD self-association is required for stable interaction with an activated death receptor.
  Cell Death Differ, 13, 2052-2061.  
16317000 F.Y.Li, P.D.Jeffrey, J.W.Yu, and Y.Shi (2006).
Crystal structure of a viral FLIP: insights into FLIP-mediated inhibition of death receptor signaling.
  J Biol Chem, 281, 2960-2968.
PDB code: 2f1s
16434054 H.H.Park, and H.Wu (2006).
Crystal structure of RAIDD death domain implicates potential mechanism of PIDDosome assembly.
  J Mol Biol, 357, 358-364.
PDB code: 2o71
16003390 L.R.Thomas, L.M.Bender, M.J.Morgan, and A.Thorburn (2006).
Extensive regions of the FADD death domain are required for binding to the TRAIL receptor DR5.
  Cell Death Differ, 13, 160-162.  
17145551 M.Pehar, M.R.Vargas, K.M.Robinson, P.Cassina, P.England, J.S.Beckman, P.M.Alzari, and L.Barbeito (2006).
Peroxynitrite transforms nerve growth factor into an apoptotic factor for motor neurons.
  Free Radic Biol Med, 41, 1632-1644.  
17139086 N.Handa, M.Kukimoto-Niino, R.Akasaka, K.Murayama, T.Terada, M.Inoue, T.Yabuki, M.Aoki, E.Seki, T.Matsuda, E.Nunokawa, A.Tanaka, Y.Hayashizaki, T.Kigawa, M.Shirouzu, and S.Yokoyama (2006).
Structure of the UNC5H2 death domain.
  Acta Crystallogr D Biol Crystallogr, 62, 1502-1509.
PDB code: 1wmg
16762833 P.E.Carrington, C.Sandu, Y.Wei, J.M.Hill, G.Morisawa, T.Huang, E.Gavathiotis, Y.Wei, and M.H.Werner (2006).
The structure of FADD and its mode of interaction with procaspase-8.
  Mol Cell, 22, 599-610.
PDB code: 2gf5
16108814 A.Takata-Tomokuni, A.Ueki, M.Shiwa, Y.Isozaki, T.Hatayama, H.Katsuyama, F.Hyodoh, W.Fujimoto, H.Ueki, M.Kusaka, H.Arikuni, and T.Otsuki (2005).
Detection, epitope-mapping and function of anti-Fas autoantibody in patients with silicosis.
  Immunology, 116, 21-29.  
16006552 C.Sandu, E.Gavathiotis, T.Huang, I.Wegorzewska, and M.H.Werner (2005).
A mechanism for death receptor discrimination by death adaptors.
  J Biol Chem, 280, 31974-31980.  
16009710 H.Z.Imtiyaz, Y.Zhang, and J.Zhang (2005).
Structural requirements for signal-induced target binding of FADD determined by functional reconstitution of FADD deficiency.
  J Biol Chem, 280, 31360-31367.  
14573612 J.M.Hill, G.Morisawa, T.Kim, T.Huang, Y.Wei, Y.Wei, and M.H.Werner (2004).
Identification of an expanded binding surface on the FADD death domain responsible for interaction with CD95/Fas.
  J Biol Chem, 279, 1474-1481.  
15173180 L.R.Thomas, A.Henson, J.C.Reed, F.R.Salsbury, and A.Thorburn (2004).
Direct binding of Fas-associated death domain (FADD) to the tumor necrosis factor-related apoptosis-inducing ligand receptor DR5 is regulated by the death effector domain of FADD.
  J Biol Chem, 279, 32780-32785.  
14668343 T.Vanden Berghe, G.van Loo, X.Saelens, M.Van Gurp, G.Brouckaert, M.Kalai, W.Declercq, and P.Vandenabeele (2004).
Differential signaling to apoptotic and necrotic cell death by Fas-associated death domain protein FADD.
  J Biol Chem, 279, 7925-7933.  
15044455 Y.Guo, N.Cheong, Z.Zhang, R.De Rose, Y.Deng, S.A.Farber, T.Fernandes-Alnemri, and E.S.Alnemri (2004).
Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death.
  J Biol Chem, 279, 24813-24825.  
15601308 Y.H.Soung, J.W.Lee, S.Y.Kim, S.W.Nam, W.S.Park, S.H.Kim, J.Y.Lee, N.J.Yoo, and S.H.Lee (2004).
Mutation of FADD gene is rare in human colon and stomach cancers.
  APMIS, 112, 595-597.  
12576135 A.Clerk, S.M.Cole, T.E.Cullingford, J.G.Harrison, M.Jormakka, and D.M.Valks (2003).
Regulation of cardiac myocyte cell death.
  Pharmacol Ther, 97, 223-261.  
12717014 D.Idiyatullin, I.Nesmelova, V.A.Daragan, and K.H.Mayo (2003).
Comparison of (13)C(alpha)H and (15)NH backbone dynamics in protein GB1.
  Protein Sci, 12, 914-922.  
  12875962 R.S.Al-Lamki, J.Wang, S.Thiru, N.R.Pritchard, J.A.Bradley, J.S.Pober, and J.R.Bradley (2003).
Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants.
  Am J Pathol, 163, 401-411.  
12185077 A.Fong, M.Zhang, J.Neely, and S.C.Sun (2002).
S9, a 19 S proteasome subunit interacting with ubiquitinated NF-kappaB2/p100.
  J Biol Chem, 277, 40697-40702.  
11839303 C.A.Andersen, A.G.Palmer, S.Brunak, and B.Rost (2002).
Continuum secondary structure captures protein flexibility.
  Structure, 10, 175-184.  
12107169 L.R.Thomas, D.J.Stillman, and A.Thorburn (2002).
Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen.
  J Biol Chem, 277, 34343-34348.  
11479427 D.Fink, H.Schlagbauer-Wadl, E.Selzer, T.Lucas, K.Wolff, H.Pehamberger, H.G.Eichler, and B.Jansen (2001).
Elevated procaspase levels in human melanoma.
  Melanoma Res, 11, 385-393.  
11231290 G.De Wilde, J.Murray-Rust, E.Boone, D.Olerenshaw, N.Q.McDonald, C.Ibanez, G.Haegeman, A.Wollmer, and M.Federwisch (2001).
Structure-activity relationship of the p55 TNF receptor death domain and its lymphoproliferation mutants.
  Eur J Biochem, 268, 1382-1391.  
11514682 W.J.Fairbrother, N.C.Gordon, E.W.Humke, K.M.O'Rourke, M.A.Starovasnik, J.P.Yin, and V.M.Dixit (2001).
The PYRIN domain: a member of the death domain-fold superfamily.
  Protein Sci, 10, 1911-1918.  
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.