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Updated: Feb 14, 2026

Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations
Published on: November 7, 2019
Mechanism of ubiquitin transfer promoted by TRAF6
Tian-Min Fu1,2, Chen Shen1,2, Qiubai Li1,2
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Abstract:
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.
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