Gene

Ubiquitin ligase

Allosteric regulation

Receptor

Organic chemistry

Ubiquitin-conjugating enzyme

Chemistry

Ubiquitin

Dimer

Ring (chemistry)

Ubiquitin-Protein Ligases

Biochemistry

Signal transduction

Biology

Cell biology

Proceedings of the National Academy of Sciences

Significance Polyubiquitination is critically important for many cellular functions from protein degradation to signal transduction. TNF receptor-associated factor 6 (TRAF6) is a RING-type ubiquitin ligase that promotes polyubiquitination required for the signaling of many innate immune receptors. How TRAF6 uses its RING dimer to facilitate polyubiquitination remains elusive. In this paper, we mapped TRAF6 residues on both subunits of the TRAF6 dimer that are required for this process via allosteric activation. We found that in addition to the RING domain itself, residues outside the RING domain play indispensable roles. Moreover, our studies reveal common features for the activation of polyubiquitination by the RING family and related domains, which shed light on the functional mechanisms of both dimeric and monomeric ubiquitin ligases.

Mechanism of ubiquitin transfer promoted by TRAF6