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TitleStructural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 4875, Year 2025
Publish dateMay 26, 2025
AuthorsMasa Janosev / Dalibor Kosek / Andrej Tekel / Rohit Joshi / Karolina Honzejkova / Pavel Pohl / Tomas Obsil / Veronika Obsilova /
PubMed AbstractNedd4-2 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 ...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, Ca-dependent C2 membrane binding disrupts C2/HECT interactions, but not Ca 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.
External linksNat Commun / PubMed:40419858 / PubMed Central
MethodsEM (single particle)
Resolution3.58 - 4.11 Å
Structure data

51373

9gik

EMDB-51373, PDB-9gik:
Full-lenght Nedd4-2 E3 ubiquitin ligase
Method: EM (single particle) / Resolution: 3.58 Å

51374

9gim

EMDB-51374, PDB-9gim:
Full-lenght Nedd4-2 E3 ubiquitin ligase in presence of Ca2+
Method: EM (single particle) / Resolution: 4.11 Å

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Nedd4-2 / calcium / 14-3-3 proteins / H/D exchange / Cryo-EM / SAXS / protein-protein interaction

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