Distinct molecular mechanism for initiating TRAF6 signalling.
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) superfamily; 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 degrees 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.
Ye
Hong
H
Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, USA.
Arron
Joseph R
JR
Lamothe
Betty
B
Cirilli
Maurizio
M
Kobayashi
Takashi
T
Shevde
Nirupama K
NK
Segal
Deena
D
Dzivenu
Oki K
OK
Vologodskaia
Masha
M
Yim
Mijung
M
Du
Khoi
K
Singh
Sujay
S
Pike
J Wesley
JW
Darnay
Bryant G
BG
Choi
Yongwon
Y
Wu
Hao
H
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019013:CD40 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D051379:Mice; D008958:Models, Molecular; D009000:Monocytes; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6
D019013:CD40 Antigens; D016328:NF-kappa B; D010446:Peptide Fragments; D011506:Proteins; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases