6YOS

Binary complex of 14-3-3 zeta with Glucocorticoid Receptor (GR) pT524 pS617 peptide

Summary for 6YOS

• Entry DOI: 10.2210/pdb6yos/pdb
• Related: 6YMO 6YO8
• Descriptor: 14-3-3 protein zeta/delta, Glucocorticoid receptor,Glucocorticoid receptor (2 entities in total)
• Functional Keywords: 14-3-3 protein zeta/delta, glucocorticoid receptor, protein-peptide complex, protein-protein interaction, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 56794.05

Authors

Munier, C.C.,Edman, K.,Perry, M.W.D.,Ottmann, C. (deposition date: 2020-04-15, release date: 2021-03-24, Last modification date: 2024-11-06)

Primary citation

Munier, C.C.,De Maria, L.,Edman, K.,Gunnarsson, A.,Longo, M.,MacKintosh, C.,Patel, S.,Snijder, A.,Wissler, L.,Brunsveld, L.,Ottmann, C.,Perry, M.W.D.
Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators.
J.Biol.Chem., 296:100551-100551, 2021

PubMed Abstract: 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.

PubMed: 33744286
DOI: 10.1016/j.jbc.2021.100551

Experimental method

X-RAY DIFFRACTION (2.75 Å)