Distinct molecular mechanism for initiating TRAF6 signalling

Hong Ye, Joseph R. Arron, Betty Lamothe, Maurizio Cirilli, Takashi Kobayashi, Nirupama K. Shevde, Deena Segal, Oki K. Dzivenu, Masha Vologodskaia, Mijung Yim, Khoi Du, Sujay Singh, J. Wesley Pike, Bryant G. Darnay, Yongwon Choi and Hao Wu ()
Additional contact information
Hong Ye: Weill Medical College of Cornell University
Joseph R. Arron: Tri-Institutional MD-PhD Program, The Rockefeller University
Betty Lamothe: The University of Texas MD Anderson Cancer Center
Maurizio Cirilli: Weill Medical College of Cornell University
Takashi Kobayashi: University of Pennsylvania School of Medicine
Nirupama K. Shevde: University of Wisconsin
Deena Segal: Weill Medical College of Cornell University
Oki K. Dzivenu: Weill Medical College of Cornell University
Masha Vologodskaia: The Rockefeller University
Mijung Yim: University of Pennsylvania School of Medicine
Khoi Du: The University of Texas MD Anderson Cancer Center
Sujay Singh: Imgenex Corporation
J. Wesley Pike: University of Wisconsin
Bryant G. Darnay: The University of Texas MD Anderson Cancer Center
Yongwon Choi: University of Pennsylvania School of Medicine
Hao Wu: Weill Medical College of Cornell University

Nature, 2002, vol. 418, issue 6896, 443-447

Abstract: Abstract Tumour-necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is the only TRAF family member that participates in signal transduction of both the TNF receptor (TNFR) superfamily and the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily1,2,3,4,5; it is important for adaptive immunity, innate immunity and bone homeostasis. Here we report crystal structures of TRAF6, alone and in complex with TRAF6-binding peptides from CD40 and TRANCE-R (also known as RANK), members of the TNFR superfamily, to gain insight into the mechanism by which TRAF6 mediates several signalling cascades. A 40° difference in the directions of the bound peptides in TRAF6 and TRAF2 shows that there are marked structural differences between receptor recognition by TRAF6 and other TRAFs. The structural determinant of the petide–TRAF6 interaction reveals a Pro-X-Glu-X-X-(aromatic/acidic residue) TRAF6-binding motif, which is present not only in CD40 and TRANCE-R but also in the three IRAK adapter kinases for IL-1R/TLR signalling. Cell-permeable peptides with the TRAF6-binding motif inhibit TRAF6 signalling, which indicates their potential as therapeutic modulators. Our studies identify a universal mechanism by which TRAF6 regulates several signalling cascades in adaptive immunity, innate immunity and bone homeostasis.

Date: 2002
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DOI: 10.1038/nature00888

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