14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains

0544647 - FGÚ 2022 RIV GB eng J - Článek v odborném periodiku
Pohl, Pavel - Joshi, Rohit - Petrvalská, Olivia - Obšil, Tomáš - Obšilová, Veronika
14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains.
Communications Biology. Roč. 4, č. 1 (2021), č. článku 899. E-ISSN 2399-3642
Grant CEP: GA ČR(CZ) GA20-00058S
Výzkumná infrastruktura: CIISB - 90043
Institucionální podpora: RVO:67985823
Klíčová slova: protein structure and function * ubiquitination * 14-3-3 protein * Nedd4-2 ubiquitin ligase * phosphorylation
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6.548, rok: 2021
Způsob publikování: Open access
https://doi.org/10.1038/s42003-021-02419-0

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 Ser342 and Ser448 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.
Trvalý link: http://hdl.handle.net/11104/0321481