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Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: implications for intracellular signaling regulation.

B cell-activating factor belonging to the TNF family receptor (BAFF-R), a member of the TNFR superfamily, plays a role in autoimmunity after ligation with BAFF ligand (also called TALL-1, BLyS, THANK, or zTNF4). BAFF/BAFF-R interactions are critical for B cell regulation, and signaling from this ligand-receptor complex results in NF-kappaB activation. Most TNFRs transmit signals intracellularly by recruitment of adaptor proteins called TNFR-associated factors (TRAFs). However, BAFF-R binds only one TRAF adaptor, TRAF3, and this interaction negatively regulates activation of NF-kappaB. In this study, we report the crystal structure of a 24-residue fragment of the cytoplasmic portion of BAFF-R bound in complex with TRAF3. The recognition motif (162)PVPAT(166) in BAFF-R is accommodated in the same binding crevice on TRAF3 that binds two related TNFRs, CD40 and LTbetaR, but is presented in a completely different structural framework. This region of BAFF-R assumes an open conformation with two extended strands opposed at right angles that each make contacts with TRAF3. The recognition motif is located in the N-terminal arm and intermolecular contacts mediate TRAF recognition. In the C-terminal arm, key stabilizing contacts are made, including critical hydrogen bonds with Gln(379) in TRAF3 that define the molecular basis for selective binding of BAFF-R solely to this member of the TRAF family. A dynamic conformational adjustment of Tyr(377) in TRAF3 occurs forming a new intermolecular contact with BAFF-R that stabilizes the complex. The structure of the complex provides a molecular explanation for binding affinities and selective protein interactions in TNFR-TRAF interactions.

Pubmed ID: 15585864


  • Ni CZ
  • Oganesyan G
  • Welsh K
  • Zhu X
  • Reed JC
  • Satterthwait AC
  • Cheng G
  • Ely KR


Journal of immunology (Baltimore, Md. : 1950)

Publication Data

December 15, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA30199
  • Agency: NCI NIH HHS, Id: CA69381
  • Agency: NIGMS NIH HHS, Id: GM57559

Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • B-Cell Activation Factor Receptor
  • B-Lymphocytes
  • Cell Line
  • Crystallography, X-Ray
  • Cytoplasm
  • DNA Mutational Analysis
  • Humans
  • Intracellular Fluid
  • Membrane Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Peptide Fragments
  • Protein Binding
  • Protein Conformation
  • Receptors, Tumor Necrosis Factor
  • Signal Transduction
  • TNF Receptor-Associated Factor 3
  • Thermodynamics