Schematic representation of the potential interaction between CD40 and its adaptor molecules. (A) CD40-mediated signaling results from a combination of both positive (right) and negative (left) signals. (B) WT CD40 (left) recruits TRAF6 in its membrane-proximal domain; TRAF1, TRAF2, TRAF3, and TRAF5 through oligomerization in the canonical TRAF2-binding site; and another TRAF2 in the C-terminus of the CD40 cytoplasmic tail. Site-directed mutagenesis resulted in the disruption of TRAF6 recruitment, much reduced TRAF2, TRAF3 binding in the canonical TRAF2 site but left the second TRAF2 site intact in ΔT2,3,6 (middle). Δ260 (right) recruits TRAF2 to the alternative site and while less likely it may also recruit other TRAF and non-TRAF molecules.