Self-regulating ubiquitin ligases

Abstract

Occasional auto‐modification of ubiquitin ligases typically leads to their proteasomal destruction, but new findings published in The EMBO Journal now show that in the case of Rsp5/Nedd4, auto‐ubiquitylation instead triggers oligomerization and concomitant reduction of ligase activity. This novel mechanism therefore creates silenced ligases that remain poised for reactivation.

Figure 1. Schematic describing how NEDD4 family ubiquitin ligases self‐regulate through auto‐ubiquitylation

Ubiquitin (UB) is transferred from a ubiquitin‐conjugating enzyme (E2) to either the Rsp5/Nedd4 active‐site cysteine and then to E3‐bound substrate, or onto a flexible α‐helix on the E3. Upon auto‐ubiquitylation of the α‐helix, the position of the helix rotates to interact with a conserved ubiquitin‐binding domain (UBD) opening access to an oligomerization domain and trimerization of Nedd4. Self‐association renders the E3 inactive.