9GIK
Full-lenght Nedd4-2 E3 ubiquitin ligase
Summary for 9GIK
| Entry DOI | 10.2210/pdb9gik/pdb |
| EMDB information | 51373 |
| Descriptor | Isoform 5 of E3 ubiquitin-protein ligase NEDD4-like (1 entity in total) |
| Functional Keywords | nedd4-2, calcium, 14-3-3 proteins, h/d exchange, cryo-em, saxs, protein-protein interaction, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 110472.95 |
| Authors | Kosek, D.,Janosev, M.,Obsil, T.,Obsilova, V. (deposition date: 2024-08-19, release date: 2025-06-04) |
| Primary citation | Janosev, M.,Kosek, D.,Tekel, A.,Joshi, R.,Honzejkova, K.,Pohl, P.,Obsil, T.,Obsilova, V. Structural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins. Nat Commun, 16:4875-4875, 2025 Cited by PubMed 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, 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. PubMed: 40419858DOI: 10.1038/s41467-025-60207-4 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.58 Å) |
Structure validation
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