Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) plays a vital 
role in immune signal transduction pathways by acting as a ubiquitin ligase (E3) 
for Lys63-linked polyubiquitin chain synthesis. However, the detailed mechanism 
by which the TRAF6 RING dimer promotes ubiquitin transfer was unknown. Through 
structural modeling and biochemical analysis, we here show that the TRAF6 RING 
dimer employs a concerted allosteric mechanism using both subunits of the TRAF6 
dimer to promote ubiquitin (Ub) transfer. In particular, we reveal the 
importance of the C-terminal extension of the TRAF6 RING domain that mediates 
trans-interactions with the donor-Ub. By analyzing structures and models of E3s 
in complex with Ub-loaded ubiquitin-conjugating enzymes (E2s), we further 
highlight the roles of N-terminal and C-terminal extensions beyond the bona fide 
RING domains in promoting Ub transfer through engagement with a donor-Ub in cis 
and in trans, respectively.