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14-3-3 蛋白通过调节 HECT 和 WW 结构域之间的相互作用来调控 Nedd4-2。

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

机构信息

Department of Structural Biology of Signaling Proteins, Division BIOCEV, Institute of Physiology of the Czech Academy of Sciences, Vestec, Czech Republic.

2nd Faculty of Medicine, Charles University, Prague, Czech Republic.

出版信息

Commun Biol. 2021 Jul 22;4(1):899. doi: 10.1038/s42003-021-02419-0.

DOI:10.1038/s42003-021-02419-0
PMID:34294877
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8298602/
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.

摘要

神经前体细胞表达的发育下调 4 连接酶（Nedd4-2）是一种 E3 泛素连接酶，可靶向蛋白质进行泛素化和内吞作用，从而调节众多离子通道、膜受体和肿瘤抑制因子。Nedd4-2 的活性受自身抑制、钙结合、氧化应激、底物结合、磷酸化和 14-3-3 蛋白结合调节。然而，14-3-3 介导的 Nedd4-2 调节的结构基础仍知之甚少。在这里，我们结合了几种综合结构生物学技术来表征 Nedd4-2 及其与 14-3-3 的复合物。我们证明磷酸化的 Ser 和 Ser 是促进 14-3-3 蛋白与 Nedd4-2 结合的关键残基，并且 14-3-3 蛋白结合通过抑制其结构域之间的相互作用诱导 Nedd4-2 的结构重排。总体而言，我们的研究结果提供了对 14-3-3 介导的 Nedd4-2 调节的结构见解，并强调了 Nedd4-2:14-3-3 复合物作为与 Nedd4-2 相关疾病（如高血压、癫痫、肾病和癌症）的药理学靶点的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/1e035adec19d/42003_2021_2419_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/6bc86dc8edbc/42003_2021_2419_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/3dd70cb450a6/42003_2021_2419_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/b7aaf3d7153b/42003_2021_2419_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/1566ffa37d3e/42003_2021_2419_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/1e035adec19d/42003_2021_2419_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/6bc86dc8edbc/42003_2021_2419_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/a5760e65274c/42003_2021_2419_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/9b992da27b8c/42003_2021_2419_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/3dd70cb450a6/42003_2021_2419_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/b7aaf3d7153b/42003_2021_2419_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/1566ffa37d3e/42003_2021_2419_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2257/8298602/1e035adec19d/42003_2021_2419_Fig7_HTML.jpg

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