Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators.
Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators.
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DOI：
10.1016/j.jbc.2021.100551
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Perry MWD
中科院分区：
文献类型：
--
作者：
Munier CC;De Maria L;Edman K;Gunnarsson A;Longo M;MacKintosh C;Patel S;Snijder A;Wissler L;Brunsveld L;Ottmann C;Perry MWD
糖皮质激素受体（GR）是一种配体依赖性转录因子，在炎症中起着重要作用。GR活性也通过蛋白质-蛋白质相互作用调节，包括由GR磷酸化诱导的14-3-3蛋白的结合。然而，GR上触发这些相互作用的特定磷酸化位点及其功能后果尚不清楚。因此，我们试图更详细地检查这个系统。我们使用磷酸化的GR肽，生物物理学研究和X射线晶体学来鉴定GR的配体结合结构域中的关键残基，T524和S617，其磷酸化导致代表性14 -3-3蛋白14-3-3结合。激酶筛选鉴定出畸形样激酶1（MINK 1）负责磷酸化T524和Rho相关蛋白激酶1磷酸化S617;基于细胞的方法证实了GR磷酸化位点和MINK 1的重要性，而不是Rho相关蛋白激酶1单独诱导GR-14-3-3结合。总之，我们的研究结果提供了对14-3-3介导的GR调节的分子水平的洞察，并强调MINK 1和GR-14-3-3轴都是未来治疗干预的潜在靶点。
The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that plays a central role in inflammation. The GR activity is also modulated via protein–protein interactions, including binding of 14-3-3 proteins induced by GR phosphorylation. However, the specific phosphorylation sites on the GR that trigger these interactions and their functional consequences are less clear. Hence, we sought to examine this system in more detail. We used phosphorylated GR peptides, biophysical studies, and X-ray crystallography to identify key residues within the ligand-binding domain of the GR, T524 and S617, whose phosphorylation results in binding of the representative 14-3-3 protein 14-3-3ζ. A kinase screen identified misshapen-like kinase 1 (MINK1) as responsible for phosphorylating T524 and Rho-associated protein kinase 1 for phosphorylating S617; cell-based approaches confirmed the importance of both GR phosphosites and MINK1 but not Rho-associated protein kinase 1 alone in inducing GR–14-3-3 binding. Together our results provide molecular-level insight into 14-3-3-mediated regulation of the GR and highlight both MINK1 and the GR–14-3-3 axis as potential targets for future therapeutic intervention.
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