Structural Basis for Self-Association and Receptor Recognition of Human TRAF2

Nature. 1999 Apr 8;398(6727):533-8. doi: 10.1038/19110.

Abstract

Tumour necrosis factor (TNF)-receptor-associated factors (TRAFs) form a family of cytoplasmic adapter proteins that mediate signal transduction from many members of the TNF-receptor superfamily and the interleukin-1 receptor. They are important in the regulation of cell survival and cell death. The carboxy-terminal region of TRAFs (the TRAF domain) is required for self-association and interaction with receptors. The domain contains a predicted coiled-coil region that is followed by a highly conserved TRAF-C domain. Here we report the crystal structure of the TRAF domain of human TRAF2, both alone and in complex with a peptide from TNF receptor-2 (TNF-R2). The structures reveal a trimeric self-association of the TRAF domain, which we confirm by studies in solution. The TRAF-C domain forms a new, eight-stranded antiparallel beta-sandwich structure. The TNF-R2 peptide binds to a conserved shallow surface depression on one TRAF-C domain and does not contact the other protomers of the trimer. The nature of the interaction indicates that an SXXE motif may be a TRAF2-binding consensus sequence. The trimeric structure of the TRAF domain provides an avidity-based explanation for the dependence of TRAF recruitment on the oligomerization of the receptors by their trimeric extracellular ligands.

MeSH terms

  • Amino Acid Sequence
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Escherichia coli
  • Humans
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Proteins / chemistry*
  • Proteins / metabolism
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Structure-Activity Relationship
  • TNF Receptor-Associated Factor 2

Substances

  • Macromolecular Substances
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 2

Associated data

  • PDB/1CA4
  • PDB/1CA9