Structural elements in the flexible tail of the co-chaperone p23 coordinate client binding and progression of the Hsp90 chaperone cycle
Copyright policy )Structural elements in the flexible tail of the co-chaperone p23 coordinate client binding and progression of the Hsp90 chaperone cycle
AbstractThe co-chaperone p23 is a central part of the Hsp90 machinery. It stabilizes the closed conformation of Hsp90, inhibits its ATPase and is important for client maturation. Yet, how this is achieved has remained enigmatic. Here, we show that a tryptophan residue in the proximal region of the tail decelerates the ATPase by allosterically switching the conformation of the catalytic loop in Hsp90. We further show by NMR spectroscopy that the tail interacts with the Hsp90 client binding site via a conserved helix. This helical motif in the p23 tail also binds to the client protein glucocorticoid receptor (GR) in the free and Hsp90-bound form. In vivo experiments confirm the physiological importance of ATPase modulation and the role of the evolutionary conserved helical motif for GR activation in the cellular context.
- Technical University of Munich (TUM) Germany
- Technical University of Munich Germany
- INSTITUT FUR MIKROBIOLOGIE DER BUNDESWEHR Germany
- Helmholtz Zentrum München Germany
Protein Conformation, alpha-Helical, Science, Adenylyl Imidodiphosphate, Genetic Vectors, Gene Expression, Molecular Dynamics Simulation, Article, Receptors, Glucocorticoid, Escherichia coli, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, HSP90 Heat-Shock Proteins, Cloning, Molecular, Nuclear Magnetic Resonance, Biomolecular, Prostaglandin-E Synthases, Binding Sites, Q, Article ; Chaperones ; Molecular conformation ; Solution-state NMR, Recombinant Proteins, Mutation, Protein Conformation, beta-Strand, Molecular Chaperones, Protein Binding, ddc: ddc:
Protein Conformation, alpha-Helical, Science, Adenylyl Imidodiphosphate, Genetic Vectors, Gene Expression, Molecular Dynamics Simulation, Article, Receptors, Glucocorticoid, Escherichia coli, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, HSP90 Heat-Shock Proteins, Cloning, Molecular, Nuclear Magnetic Resonance, Biomolecular, Prostaglandin-E Synthases, Binding Sites, Q, Article ; Chaperones ; Molecular conformation ; Solution-state NMR, Recombinant Proteins, Mutation, Protein Conformation, beta-Strand, Molecular Chaperones, Protein Binding, ddc: ddc:
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