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@article{1846844,
author = {Pohl, P. and Joshi, R. and Petrvalska, O. and Obsil, T. and Obsilova, V.},
article_number = {1},
doi = {http://dx.doi.org/10.1038/s42003-021-02419-0},
keywords = {EPITHELIAL NA+ CHANNELPROTEIN-PROTEIN INTERACTIONSSTRUCTURAL BASISPROTEOMIC ANALYSISSODIUM-CHANNELSMOLECULAR-BASISPY MOTIFPHOSPHORYLATIONBINDINGSERUM},
language = {eng},
issn = {2399-3642},
journal = {COMMUNICATIONS BIOLOGY},
title = {14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains},
url = {https://www.nature.com/articles/s42003-021-02419-0.pdf},
volume = {4},
year = {2021}
}
TY - JOUR
ID - 1846844
AU - Pohl, P. - Joshi, R. - Petrvalska, O. - Obsil, T. - Obsilova, V.
PY - 2021
TI - 14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains
JF - COMMUNICATIONS BIOLOGY
VL - 4
IS - 1
SP - 899
EP - 899
SN - 23993642
KW - EPITHELIAL NA+ CHANNELPROTEIN-PROTEIN INTERACTIONSSTRUCTURAL BASISPROTEOMIC ANALYSISSODIUM-CHANNELSMOLECULAR-BASISPY MOTIFPHOSPHORYLATIONBINDINGSERUM
UR - https://www.nature.com/articles/s42003-021-02419-0.pdf
N2 - 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(342) and Ser(448) 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. Pohl et al. investigated the structural basis of Nedd4-2 regulation by 14-3-3 and found that phosphorylated Ser342 and Ser448 are the main residues that facilitate 14-3-3 binding to Nedd4-2. The authors propose that the Nedd4-2:14-3-3 complex then stimulates a structural rearrangement of Nedd4-2 through inhibiting interaction of its structured domains.
ER -
POHL, P., R. JOSHI, O. PETRVALSKA, T. OBSIL and V. OBSILOVA. 14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains. \textit{COMMUNICATIONS BIOLOGY}. 2021, vol.~4, No~1, p.~899-913. ISSN~2399-3642. Available from: https://dx.doi.org/10.1038/s42003-021-02419-0.
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