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

SYSNO ASEP	0544647
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains
Author(s)	Pohl, Pavel (FGU-C)_ORCID Joshi, Rohit (FGU-C) Petrvalská, Olivia (FGU-C)_{RID, ORCID, SAI} Obšil, Tomáš (FGU-C)_{RID, ORCID} Obšilová, Veronika (FGU-C)_{RID, ORCID, SAI}
Article number	899
Source Title	Communications Biology. - : Nature Publishing Group Roč. 4, č. 1 (2021)
Number of pages	15 s.
Language	eng - English
Country	GB - United Kingdom
Keywords	protein structure and function ; ubiquitination ; 14-3-3 protein ; Nedd4-2 ubiquitin ligase ; phosphorylation
Subject RIV	CE - Biochemistry
OECD category	Biochemistry and molecular biology
R&D Projects	GA20-00058S GA ČR - Czech Science Foundation (CSF)
Research Infrastructure	CIISB - 90043 - Masarykova univerzita
Method of publishing	Open access
Institutional support	FGU-C - RVO:67985823
UT WOS	000680395000002
EID SCOPUS	85111089437
DOI	10.1038/s42003-021-02419-0
Annotation	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.
Workplace	Institute of Physiology
Contact	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Year of Publishing	2022
Electronic address	https://doi.org/10.1038/s42003-021-02419-0

Number of the records: 1