PDBsum entry: 1flk

Apoptosis

PDB id: 1flk

Contents

Protein chains

205 a.a. *

* Residue conservation analysis

PDB id:

1flk

Name:

Apoptosis

Title:

Molecular basis for cd40 signaling mediated by traf3

Structure:

Tnf receptor associated factor 3. Chain: a, b. Fragment: traf domain. Engineered: yes

Source:

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

Biol. unit:

Trimer (from PDB file)

Resolution:

2.80Å R-factor: 0.224 R-free: 0.286

Authors:

C.-Z.Ni,K.Welsh,E.Leo,C.-K.Chiou,H.Wu,J.C.Reed,K.R.Ely

Key ref:

C.Z.Ni et al. (2000). Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci U S A, 97, 10395-10399. PubMed id: 10984535 DOI: 10.1073/pnas.97.19.10395

Date:

14-Aug-00 Release date: 18-Oct-00

Protein chains

Q13114  (TRAF3_HUMAN) -  TNF receptor-associated factor 3

Seq: 568 a.a.

Struc: 205 a.a.

 Gene Ontology (GO) functional annotation 

• Biochemical function: protein binding (1 term)

DOI no: 10.1073/pnas.97.19.10395

Proc Natl Acad Sci U S A 97:10395-10399 (2000)

PubMed id: 10984535

Molecular basis for CD40 signaling mediated by TRAF3.

C.Z.Ni, K.Welsh, E.Leo, C.K.Chiou, H.Wu, J.C.Reed, K.R.Ely.

ABSTRACT

Tumor necrosis factor receptors (TNFR) are single transmembrane-spanning glycoproteins that bind cytokines and trigger multiple signal transduction pathways. Many of these TNFRs rely on interactions with TRAF proteins that bind to the intracellular domain of the receptors. CD40 is a member of the TNFR family that binds to several different TRAF proteins. We have determined the crystal structure of a 20-residue fragment from the cytoplasmic domain of CD40 in complex with the TRAF domain of TRAF3. The CD40 fragment binds as a hairpin loop across the surface of the TRAF domain. Residues shown by mutagenesis and deletion analysis to be critical for TRAF3 binding are involved either in direct contact with TRAF3 or in intramolecular interactions that stabilize the hairpin. Comparison of the interactions of CD40 with TRAF3 vs. TRAF2 suggests that CD40 may assume different conformations when bound to different TRAF family members. This molecular adaptation may influence binding affinity and specific cellular triggers.

Selected figure(s)

Figure 1.
Fig. 1. The overall structure of the TRAF3 subunit is composed of an elongated helix followed by an eight-stranded -sandwich (TRAF domain). (A) Superimposition of the polypeptide backbone of the C-terminal TRAF domain of TRAF3 (red) and TRAF2 (24). The rms deviation between corresponding -carbons is 1 Å. Strong homology (59% identical) exists between TRAF3 and TRAF2 in this domain. The sandwich is formed by two layers of -sheet, each with four antiparallel strands. The topology of this -sandwich is found thus far only in TRAF domains. (B) The TRAF-N domain of TRAF3 is a long amphipathic -helix that forms a coiled-coil when TRAF3 trimerizes (see Fig. 3). Residues 300-347 were ordered in the electron density map. The coiled-coil interactions are stabilized by nine heptad repeats of hydrophobic residues. This hydrophobic pattern is interrupted at residues 324 and 331 where three histidines are found in the interior of the coiled-coil. The side chains of these histidines extend out of the coiled-coil. The TRAF3 fragment is considerably longer at the N terminus than the TRAF2 fragment, where residues from the N terminus were missing or disordered (24, 33). This model provides structural details for most of the helical TRAF-N region.

Figure 3.
Fig. 3. TRAF3/CD40 interactions. (A) Schematic drawing of the TRAF3 trimer with the polypeptide backbone of TRAF3 presented as a ribbon model and the CD40 peptide shown as a ball and stick model. One CD40 fragment binds to each TRAF3 monomer at the edge of the TRAF3 domain, crossing one -sheet. No conformational changes were seen when comparing TRAF3 alone or bound to CD40. (B) Close-up view of the CD40 fragment bound to TRAF2 and TRAF3. Residues in CD40 are labeled, and critical contact residues in TRAF3 are also marked and underlined for identification. Interactions within 3.0 Å that are proposed to dictate specific recognition of CD40 and TRAF3 or TRAF2 are shown as dotted lines. The images show intramolecular hydrogen bonds within the CD40 fragment that stabilize the reverse turn (Middle) and direct contacts between CD40 and TRAF3 (Bottom). These images can be contrasted with the contacts in TRAF2 (Top; 1CZZ-; based on figure 3 of Ye et al. in ref. 34).

Figures were selected by an automated process.