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.