• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

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

Authors

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

Journal

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