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Structural basis for self-association and receptor recognition of human TRAF2

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 receptor1. 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 domain2. 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 β-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.

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Figure 1: Structure of the TRAF domain alone and in complex with the TNF-R2 peptide.
Figure 2: Structure-based sequence alignment of TRAF-family members.
Figure 3: Detailed interaction between TRAF2 and the TNF-R2 peptide.

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Acknowledgements

We thank W. Hendrickson for discussions; T. Burling for maintaining the X-ray equipment and computers; C. Ogata for assistance at the X4A beamline of NSLS; members of the CHESS for help at the F2 beamline; M. Lu for running the analytical ultracentrifugation experiments; C. Lima for help with the SETOR program; and G. Douglas and M. Cervantes for summer research in the laboratory.

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Correspondence to Hao Wu.

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Park, Y., Burkitt, V., Villa, A. et al. Structural basis for self-association and receptor recognition of human TRAF2. Nature 398, 533–538 (1999). https://doi.org/10.1038/19110

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