6ymo
From Proteopedia
Binary complex of 14-3-3 zeta with Glucocorticoid Receptor (GR) pS617 peptide
Structural highlights
Function1433Z_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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 14-3-3zeta. 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. Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators.,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 J Biol Chem. 2021 Jan-Jun;296:100551. doi: 10.1016/j.jbc.2021.100551. Epub 2021 , Mar 17. PMID:33744286[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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