Downstream regulator TANK binds to the CD40 recognition site on TRAF3.
TRAFs (tumor necrosis factor receptor [TNFR]-associated factors) bind to the cytoplasmic portion of liganded TNFRs and stimulate activation of NF-kappaB or JNK pathways. A modulator of TRAF signaling, TANK, serves as either an enhancer or an inhibitor of TRAF-mediated signaling pathways. The crystal structure of a region of TANK bound to TRAF3 has been determined and compared to a similar CD40/TRAF3 complex. TANK and CD40 bind to the same crevice on TRAF3. The recognition motif PxQxT is presented in a boomerang-like structure in TANK that is markedly different from the hairpin loop that forms in CD40 upon binding to TRAF3. Critical TANK contact residues were confirmed by mutagenesis to be required for binding to TRAF3 or TRAF2. Binding affinity, measured by isothermal titration calorimetry and competition assays, demonstrated that TANK competes with CD40 for the TRAF binding site.
Li
Chenglong
C
Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
Ni
Chao-Zhou
CZ
Havert
Marnie L
ML
Cabezas
Edelmira
E
He
Jeannie
J
Kaiser
Donald
D
Reed
John C
JC
Satterthwait
Arnold C
AC
Cheng
Genhong
G
Ely
Kathryn R
KR
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D023201:CD40 Ligand / Q000737:chemistry / Q000378:metabolism*; D002151:Calorimetry; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D017354:Point Mutation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D048008:TNF Receptor-Associated Factor 3
D048868:Adaptor Proteins, Signal Transducing; D011506:Proteins; D011993:Recombinant Fusion Proteins; C484406:TANK protein, human; D048008:TNF Receptor-Associated Factor 3; D023201:CD40 Ligand