6ZC9

Structure of 14-3-3 gamma in complex with Nedd4-2 14-3-3 binding motif Ser448

Summary for 6ZC9

• Entry DOI: 10.2210/pdb6zc9/pdb
• Descriptor: 14-3-3 protein gamma, E3 ubiquitin-protein ligase NEDD4-like, 1,1,1,3,3,3-hexafluoropropan-2-ol, ... (4 entities in total)
• Functional Keywords: e3 ubiquitin protein ligase, complex, phosphorylation, 14-3-3 protein, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 113190.44

Authors

Pohl, P.,Kalabova, D.,Obsil, T.,Obsilova, V. (deposition date: 2020-06-10, release date: 2021-07-21, Last modification date: 2024-10-23)

Primary citation

Pohl, P.,Joshi, R.,Petrvalska, O.,Obsil, T.,Obsilova, V.
14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains.
Commun Biol, 4:899-899, 2021

PubMed Abstract: Neural precursor cell expressed developmentally down-regulated 4 ligase (Nedd4-2) is an E3 ubiquitin ligase that targets proteins for ubiquitination and endocytosis, thereby regulating numerous ion channels, membrane receptors and tumor suppressors. Nedd4-2 activity is regulated by autoinhibition, calcium binding, oxidative stress, substrate binding, phosphorylation and 14-3-3 protein binding. However, the structural basis of 14-3-3-mediated Nedd4-2 regulation remains poorly understood. Here, we combined several techniques of integrative structural biology to characterize Nedd4-2 and its complex with 14-3-3. We demonstrate that phosphorylated Ser and Ser are the key residues that facilitate 14-3-3 protein binding to Nedd4-2 and that 14-3-3 protein binding induces a structural rearrangement of Nedd4-2 by inhibiting interactions between its structured domains. Overall, our findings provide the structural glimpse into the 14-3-3-mediated Nedd4-2 regulation and highlight the potential of the Nedd4-2:14-3-3 complex as a pharmacological target for Nedd4-2-associated diseases such as hypertension, epilepsy, kidney disease and cancer.

PubMed: 34294877
DOI: 10.1038/s42003-021-02419-0

Experimental method

X-RAY DIFFRACTION (1.89895988606 Å)