Structural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins

Masa Janosev, Dalibor Kosek, Andrej Tekel, Rohit Joshi, Karolina Honzejkova, Pavel Pohl, Tomas Obsil () and Veronika Obsilova ()
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Masa Janosev: Division BIOCEV
Dalibor Kosek: Division BIOCEV
Andrej Tekel: Division BIOCEV
Rohit Joshi: Division BIOCEV
Karolina Honzejkova: Charles University
Pavel Pohl: Division BIOCEV
Tomas Obsil: Division BIOCEV
Veronika Obsilova: Division BIOCEV

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Nedd4-2 E3 ligase regulates Na+ homeostasis by ubiquitinating various channels and membrane transporters, including the epithelial sodium channel ENaC. In turn, Nedd4-2 dysregulation leads to various conditions, including electrolytic imbalance, respiratory distress, hypertension, and kidney diseases. However, Nedd4-2 regulation remains mostly unclear. The present study aims at elucidating Nedd4-2 regulation by structurally characterizing Nedd4-2 and its complexes using several biophysical techniques. Our cryo-EM reconstruction shows that the C2 domain blocks the E2-binding surface of the HECT domain. This blockage, ubiquitin-binding exosite masking by the WW1 domain, catalytic C922 blockage and HECT domain stabilization provide the structural basis for Nedd4-2 autoinhibition. Furthermore, Ca2+-dependent C2 membrane binding disrupts C2/HECT interactions, but not Ca2+ alone, whereas 14-3-3 protein binds to a flexible region of Nedd4-2 containing the WW2 and WW3 domains, thereby inhibiting its catalytic activity and membrane binding. Overall, our data provide key mechanistic insights into Nedd4-2 regulation toward fostering the development of strategies targeting Nedd4-2 function.

Date: 2025
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DOI: 10.1038/s41467-025-60207-4

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