Crystal Structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 Complexes: Affinity, Specificity, and Regulation

TRAF1/2 and cIAP1/2 are members of the TNF receptor associated factor (TRAF) and the inhibitor of apoptosis (IAP) families, respectively. They are critical for both the canonical and the noncanonical NF-κB signaling pathways. Here we report the crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes. A TRAF2 trimer interacts with one cIAP2 both in the crystal and in solution. Two chains of the TRAF2 trimer directly contact cIAP2 and key residues at the interface are confirmed by mutagenesis both in vitro and in cells. TRAF1 and TRAF2 preferentially form the TRAF1: (TRAF2)2 heterotrimer, which interacts with cIAP2 more strongly than TRAF2 alone. In contrast, TRAF1 alone interacts very weakly with cIAP2. Surprisingly, TRAF1 and one chain of TRAF2 in the TRAF1: (TRAF2)2: cIAP2 ternary complex mediate interaction with cIAP2. Because TRAF1 is dramatically upregulated by many stimuli, it may modulate the interaction of TRAF2 with cIAP1/2, which explains previously noted regulatory roles of TRAF1 in TNF signaling.