New Angle on TRAF6 Signaling

Science's STKE  30 Jul 2002:
Vol. 2002, Issue 143, pp. tw273-TW273
DOI: 10.1126/stke.2002.143.tw273

The TRAFs are adaptor proteins that function in signaling from cytokine receptors. In particular, TRAF6 takes part in signaling by the tumor necrosis factor (TNF) receptor and the interleukin 1 (or Toll-like) receptor. Ye et al. examined the interaction interface between TRAF6 and peptides from two TNF receptor family members, CD40 and TRANCE-R (tumor necrosis factor-related, activation-induced cytokine receptor, also called RANK) by x-ray crystallography. The binding interaction was substantially different from that of other TRAF family members with these receptors. There is a 40° difference in the orientation of the peptide and TRAF molecules, which means that there are major differences in the amino acid interactions that account for the binding. The authors established a TRAF6-binding motif [Pro-X-Glu-XX-(AR-AC), where X is any amino acid and AR-AC is an aromatic or acidic residue]. This motif was also shown to mediate interaction of TRAF6 with IRAK (interleukin-1 receptor-associated kinase), which links the IL-1 receptor to activation of downstream kinases. Searches for the presence of this motif turned up another potential interaction partner, the protein kinase RIP2 (receptor-interacting protein 2, also known as RICK, CARDIAK, CCK, or Ripk2), which also functions in signaling from TNF and IL-1 receptors. Cell-permeable peptides containing the TRAF6-binding motif blocked signaling through TRAF6, indicating that interruption of these interactions may provide a therapeutic strategy for specifically modulating signaling through TRAF6, which has critical roles in both innate and adaptive immunity and control of bone resorption.

H. Ye, J. R. Arron, B. Lamothe, M. Cirilli, T. Kobayashi, N. K. Shevde, D. Segal, O. K. Dzivenu, M. Vologodskaia, M. Yim, K. Du, S. Singh, J. W. Pike, B. G. Darnay, Y. Choi, H. Wu, Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418, 443-447 (2002). [Online Journal]