PDBsum entry 1f3v

Apoptosis

PDB id: 1f3v

Contents

Protein chains

158 a.a. *

171 a.a. *

Waters ×208

* Residue conservation analysis

PDB id:

1f3v

Name:

Apoptosis

Title:

Crystal structure of the complex between the n-terminal domain of tradd and the traf domain of traf2

Structure:

Tumor necrosis factor receptor type 1 associated death domain protein. Chain: a. Fragment: n-terminal domain. Synonym: tradd, tnfr1-associated death domain protein. Engineered: yes. Tumor necrosis factor receptor-associated protein. Chain: b. Fragment: traf domain.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Hexamer (from PQS)

Resolution:

2.00Å R-factor: 0.229 R-free: 0.261

Authors:

Y.C.Park,H.Ye,C.Hsia,D.Segal,R.Rich,H.-C.Liou,D.Myszka,H.Wu

Key ref:

Y.C.Park et al. (2000). A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Cell, 101, 777-787. PubMed id: 10892748 DOI: 10.1016/S0092-8674(00)80889-2

Date:

06-Jun-00 Release date: 06-Sep-00

Protein chain

Q15628  (TRADD_HUMAN) -  Tumor necrosis factor receptor type 1-associated DEATH domain protein from Homo sapiens

Seq: 312 a.a.

Struc: 158 a.a.

Protein chain

Q12933  (TRAF2_HUMAN) -  TNF receptor-associated factor 2 from Homo sapiens

Seq: 501 a.a.

Struc: 171 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chain B: E.C.2.3.2.27 - RING-type E3 ubiquitin transferase.
• 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: 10.1016/S0092-8674(00)80889-2

Cell 101:777-787 (2000)

PubMed id: 10892748

A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction.

Y.C.Park, H.Ye, C.Hsia, D.Segal, R.L.Rich, H.C.Liou, D.G.Myszka, H.Wu.

ABSTRACT

TRAF proteins are major mediators for the cell activation, cell survival, and antiapoptotic functions of the TNF receptor superfamily. They can be recruited to activated TNF receptors either by direct interactions with the receptors or indirectly via the adaptor protein TRADD. We now report the structure of the TRADD-TRAF2 complex, which is highly distinct from receptor-TRAF2 interactions. This interaction is significantly stronger and we show by an in vivo signaling assay that TRAF2 signaling is more readily initiated by TRADD than by direct receptor-TRAF2 interactions. TRADD is specific for TRAF1 and TRAF2, which ensures the recruitment of clAPs for the direct inhibition of caspase activation in the signaling complex. The stronger affinity and unique specificity of the TRADD-TRAF2 interaction are crucial for the suppression of apoptosis and provide a mechanistic basis for the perturbation of TRAF recruitment in sensitizing cell death induction.

Selected figure(s)

Figure 1.
Figure 1. Structural Overview of TRADD-N and the TRADD-N/TRAF2 Complex(A) Ribbon representation of TRADD-N, showing the two-layer arrangement of the α-β sandwich. Helices are colored yellow (A-F), β strands blue (1–4), and loops green. The β sheet is entirely antiparallel and slightly twisted with a strand order of β2, β3, β1, and β4. There are two helices each in the β1-β2 and β3-β4 cross-over connections while the β2-β3 connection is hairpin-like. The remaining two helices (E and F) are near the carboxyl terminus of the domain; the loop in between (EF loop) partly covers one end of the exposed face of the β sheet. A single hydrophobic core is present in TRADD-N between the buried face of the β sheet and the opposing α helices. The closed nature of this hydrophobic core supports that this domain folds independently of the carboxy-terminal death domain.(B and C) Ribbon representations of the TRADD-N/TRAF2 complex, showing with the 3-fold axis vertical in (B) and into the page in (C). Three molecules of TRADD-N are shown respectively in magenta, red, and yellow. The protomers of the trimeric TRAF domain of TRAF2 are shown respectively in cyan, green, and dark blue. The death domain of TRADD (TRADD-C) is proposed to be locate above the C-terminal helix of TRADD-N in (B).(D) A hypothetical molecular arrangement in the signaling complex of TNFR1 and related death receptors. The cell membrane is represented in yellow. The trimeric TNFα, shown by ovals, mediates TNFR1 trimerization. TNFR1 is shown by straight rectangles, while FADD and RIP are shown by bent rectangles. Death domains in TNFR1, TRADD (labeled as TRADD-C), FADD, and RIP are shaded in gray. TRADD-N and the TRAF domain of TRAF2 are highlighted using the same color-coding in (B) and (C). cIAPs (oval shape) are recruited by TRAF2 and shown to inhibit caspase activation by this signaling complex. For clarity, only single molecules of FADD and RIP are shown, even though they are expected to multimerize in the signaling complex.

Figure 3.
Figure 3. Energetics of the Interaction(A) Mapping of structural features onto the TRADD-N sequence. The first line is human TRADD and the second line is mouse TRADD with identical residues shown as dashes. Solvent accessibility of each TRADD-N residue when the TRAF2 structure is pulled away is shaded below the sequences. Residues involved in TRAF2 interaction are colored based on their total surface area burials and those completely buried at the interface are labeled by asterisks. TRADD residues involved in TRAF2 interaction are almost entirely identical between the human and mouse sequences, suggesting a functional conservation among the mammalian species.(B) Characterization of the interactions of wild-type and mutant TRADD-N with wild-type TRAF domain of TRAF2 using biosensor analysis. The dissociation constants (K[D]) in μM and relative to the wild-type interaction are shown, as well as the calculated ΔΔG of the mutational effects (25°C).(C) TRAF2-interacting surface of TRADD-N. Region I is shown in cold colors (light blue, blue, dark blue, green, and purple) and region II in different shades of red. Colors for each mutated residue follow the same text color in (B).

The above figures are reprinted by permission from Cell Press: Cell (2000, 101, 777-787) copyright 2000.

Figures were selected by an automated process.