Nature communications, 2018-10, Vol.9 (1), p.4532-13, Article 4532
2018
Details
- Autor(en) / Beteiligte
- Titel
- Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex
- Ist Teil von
- Nature communications, 2018-10, Vol.9 (1), p.4532-13, Article 4532
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- The molecular chaperone Hsp90 is critical for the maintenance of cellular homeostasis and represents a promising drug target. Despite increasing knowledge on the structure of Hsp90, the molecular basis of substrate recognition and pro-folding by Hsp90/co-chaperone complexes remains unknown. Here, we report the solution structures of human full-length Hsp90 in complex with the PPIase FKBP51, as well as the 280 kDa Hsp90/FKBP51 complex bound to the Alzheimer's disease-related protein Tau. We reveal that the FKBP51/Hsp90 complex, which synergizes to promote toxic Tau oligomers in vivo, is highly dynamic and stabilizes the extended conformation of the Hsp90 dimer resulting in decreased Hsp90 ATPase activity. Within the ternary Hsp90/FKBP51/Tau complex, Hsp90 serves as a scaffold that traps the PPIase and nucleates multiple conformations of Tau's proline-rich region next to the PPIase catalytic pocket in a phosphorylation-dependent manner. Our study defines a conceptual model for dynamic Hsp90/co-chaperone/client recognition.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-018-06880-0Titel-ID: cdi_doaj_primary_oai_doaj_org_article_3a370245b8a44bedbc69cc4763edff90
- Format
- –
- Schlagworte
- Adenosine triphosphatase, Alzheimer's disease, Binding sites, Biocatalysis - drug effects, Biocompatibility, Catalysis, Chemistry, Dimers, Homeostasis, HSP90 Heat-Shock Proteins - chemistry, HSP90 Heat-Shock Proteins - metabolism, HSP90 Heat-Shock Proteins - toxicity, Hsp90 protein, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular structure, Neurosciences, NMR, Nuclear magnetic resonance, Oligomers, Peptidylprolyl isomerase, Phosphorylation, Phosphorylation - drug effects, Proline, Protein Binding - drug effects, Protein Conformation, Proteins, Recognition, Substrates, Tacrolimus Binding Proteins - chemistry, Tacrolimus Binding Proteins - metabolism, Tacrolimus Binding Proteins - toxicity, Tau protein, tau Proteins - chemistry, tau Proteins - metabolism, tau Proteins - toxicity