Lock, relax, load, and shoot: a molecular perspective on Nedd4 regulation

The Nedd4 subfamily of HECT E3 ligases is a ubiquitous group of 10 enzymes that share the same domain structure, consisting of a C2 domain, several WW domains and a catalytic HECT domain. Over the past decade, significant progress has been made in characterizing the molecular details of their activity and regulation. Studies have shown that, in the inactive state, the HECT domain is shielded by its N-terminal domains, thereby blocking access to the active site. The catalytic functions of Nedd4 enzymes include accepting ubiquitin molecules from ubiquitin-conjugating enzymes, transferring them to substrates, and generating diverse polyubiquitin chains. The modulation of Nedd4 enzyme activity involves mechanisms that facilitate enzymatic activation, relay binding to components of the enzymatic cascade, and enable (auto)ubiquitination. This minireview provides a comprehensive overview of the structural features distinguishing the inactive and active conformations in this group of E3 ligases, while underscoring the need for further research necessary to develop pharmaceutical solutions targeting pathological conditions rooted in Nedd4 dysfunction.