Structural Basis for the Lack of E2 Interaction in the RING Domain of TRAF2

TRAF proteins are intracellular signal transducers for if number of immune receptor super-families Specifically, TRAF2 interacts with members of the TNF receptor superfamily and connects the receptors to downstream signaling proteins It has been assumed that TRAF2 is a ubrquitin ligase like TRAF6 and mediates K63-linked polyubiquitination of RIPI, I kinase pivotal in TNF alpha-induced NF-kappa B activation Here we report the crystal structure of the RING and the first zine finger domains of TRAF2. We show that the TRAF2 RING structure is very different from the known TRAF6 RING SO LICtIll-C The differences are multifaceted, including amino acid differences at the critical Ubc 13-interacting, site, local conformational differences, and a unique nine-residue insertion between the RING domain and the first zinc finger in TRAF2 These structural differences prevent TRAF2 from interacting with Ubc 13 and other related E2s via steric clash and unfavorable interfaces. Our structural observation shou Id prompt a re-evaluation of the role of TRAF2 fit TNF alpha signaling and may indicate that TRAF2-associated proteins such as cIAPs may be the ubiquitin ligases for NF-kappa B signaling