Author
Listed:
- Hong Ye
(Weill Medical College of Cornell University)
- Joseph R. Arron
(Tri-Institutional MD-PhD Program, The Rockefeller University
University of Pennsylvania School of Medicine)
- Betty Lamothe
(The University of Texas MD Anderson Cancer Center
Yale University)
- Maurizio Cirilli
(Weill Medical College of Cornell University
Istituto di Strutturistica Chimica ‘Giordano Giacomello’, CNR, CP 10)
- 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)
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.
Suggested Citation
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. Wesl, 2002.
"Distinct molecular mechanism for initiating TRAF6 signalling,"
Nature, Nature, vol. 418(6896), pages 443-447, July.
Handle:
RePEc:nat:nature:v:418:y:2002:i:6896:d:10.1038_nature00888
DOI: 10.1038/nature00888
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Cited by:
- Fabian Giehler & Michael S. Ostertag & Thomas Sommermann & Daniel Weidl & Kai R. Sterz & Helmut Kutz & Andreas Moosmann & Stephan M. Feller & Arie Geerlof & Brigitte Biesinger & Grzegorz M. Popowicz &, 2024.
"Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex,"
Nature Communications, Nature, vol. 15(1), pages 1-18, December.
- Wenjun Xiong & Xueliang Gao & Tiantian Zhang & Baishan Jiang & Ming-Ming Hu & Xia Bu & Yang Gao & Lin-Zhou Zhang & Bo-Lin Xiao & Chuan He & Yishuang Sun & Haiou Li & Jie Shi & Xiangling Xiao & Bolin X, 2022.
"USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy,"
Nature Communications, Nature, vol. 13(1), pages 1-17, December.
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