TRAF2-Receptor Interactions Establishment of the Paradigm

Despite the high degree of sequence variation in the receptor peptides the structures surprisingly revealed that the peptides have a conserved binding mode and share a common binding site on the TRAP domain. 

The formation of a /3-sheet has been frequently observed in protein-peptide interactions, such as substrate recognition by certain serine proteases (Tong et at, 1998) and peptide recognition by the PTB and PDZ domains (Kuriyan and Cowbum, 1997). Detailed analysis further revealed that the central portion of the receptor peptide (P 2 Po  

Pi positions) is more twisted than a regular /3-strand to possess the polyproline II (PPII) helix conformation. The PPII conformation is also frequently used in protein-peptide interactions such as those seen in the peptide recognition by SH3 domains (Lim et at, 1994) and class II MHC molecules (Stem et at, 1994). This conformation allows the peptide chain to twist in order to maximize the interaction of its side chains with a protein surface. As a consequence, large proportions of the side chains at the P 2 Po 3.nd Pi positions of the receptor peptides are buried at the TRAF2 interface. Therefore, in the case of TRAF2-receptor interactions, the main chain hydrogen bonds and the PPII conformation maximize both main chain and side chain interactions with the TRAF2 surface. 

Key Residues and the Universal Major TRAF2 Binding Motif 

The sequence and structural conservations at the P 2, Po Pi positions define a major TRAF2 binding motif that bears the consensus sequence of px(Q/E)E, in which Pro is shown in lower case because it can be substituted for other medium sized non-charged residues. Most of the binding sequences identified so far for TRAFl, 2, 3, and 5 are consistent with the motif, thereby explaining the recognition of diverse receptor sequences by TRAF2 (Fig. 6). 

---