Abstract

The cell activation, cell survival, and antiapoptotic functions of the tumor necrosis factor (TNF) receptor superfamily are mostly mediated by the family of the TNF receptor-associated factors (TRAF1-6). The TRAF proteins are found in mammals, drosophila, C.elegans, and Dictyostelium discoideum. Most of the biological effects are mediated by the activation of the transcriptional factor NF-kB and Ap-1 family, which can turn on numerous genes involved in various aspects of cellular and immune functions.
TRAF2 was isolated biochemically from the TNFR-2 signaling complex and is the prototype of the six TRAF family members. Beside TNFR-2, a number of other TNFRs such as CD30, CD40, CD27, Ox40, 4-1BB, and ATAR also recruit TRAF2. In addition, the transforming effect of the Epstein-Barr virus (EBV) oncoprotein latent infection membrane protein-1 (LMP1) is partly TRAF2 mediated. Several linear consensus sequences have been proposed to bind to TRAF2, including PXQX[TSD] motif in LMP1, CD30, CD40, and CD27; the phiSXEE ( phi = large hydrophobic) sequence in TNFR-2 and CD30; and the QEE motif in 4-1BB and Ox40 receptors.
Despite the apparent sequence diversity, the receptor peptides bind to a common site on the surface of the TRAF domain of TRAF2. Crystal structures of the human TRAF2 domain in complex with peptides from the TNFR family members revealed a conserved binding mode and allowed to identify two consensus sequences.