The Structure and Ubiquitin Binding Properties of TRAF RING Heterodimers

Tumour necrosis factor (TNF) receptor associated factor (TRAF) family members share a common domain architecture, but play non-redundant physiological roles in cell signalling. At the N terminus, most TRAFs have a RING domain, followed by a series of Zinc finger (ZF) domains. The RING domain of TRAF6 dimerizes, and the RING homodimer together with the first ZF assembles ubiquitin chains that form a platform which facilitates activation of downstream kinases. The RING dimer interface is conserved amongst TRAF proteins, suggesting that functional heterodimers could be possible. Here we report the structure of the TRAF5-TRAF6 RING heterodimer, which accounts for the stability of the heterodimer as well as its ability to assemble ubiquitin chains. We also show that the RING domain of TRAF6 heterodimerizes with TRAF3 and TRAF2, and demonstrate that the linker helix and first ZF of TRAF2 can cooperate with TRAF6 to promote chain assembly. Collectively our results suggest that TRAF RING homo- and hetero-dimers have the potential to bridge interaction of nearby TRAF trimers and modulate TRAF-mediated signalling. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

Members of the TRAF family share a common domain architecture but play distinct physiological roles in cell signaling. The RING domain of TRAF6 forms homodimers and heterodimers with TRAF3 and TRAF2, promoting ubiquitin chain assembly. Both homo- and hetero-dimers of TRAF have the potential to modulate TRAF-mediated signaling by interacting with nearby TRAF trimers.