Home > Publications Database > Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex. > print

001     140308
005     20240501120103.0
024 7 _ |a 10.1038/s41467-018-06880-0
|2 doi
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024 7 _ |a pmc:PMC6208366
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037 _ _ |a DZNE-2020-06630
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Oroz, Javier
|0 P:(DE-2719)2810826
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|u dzne
245 _ _ |a Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex.
260 _ _ |a [London]
|c 2018
|b Nature Publishing Group UK
264 _ 1 |3 online
|2 Crossref
|b Springer Science and Business Media LLC
|c 2018-10-31
264 _ 1 |3 print
|2 Crossref
|b Springer Science and Business Media LLC
|c 2018-12-01
336 7 _ |a article
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336 7 _ |a Output Types/Journal article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
536 _ _ |a 342 - Disease Mechanisms and Model Systems (POF3-342)
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542 _ _ |i 2018-10-31
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|u https://creativecommons.org/licenses/by/4.0
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a HSP90 Heat-Shock Proteins
|2 NLM Chemicals
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 7 |a Tacrolimus Binding Proteins
|0 EC 5.2.1.-
|2 NLM Chemicals
650 _ 7 |a tacrolimus binding protein 5
|0 EC 5.2.1.8
|2 NLM Chemicals
650 _ 2 |a Biocatalysis: drug effects
|2 MeSH
650 _ 2 |a HSP90 Heat-Shock Proteins: chemistry
|2 MeSH
650 _ 2 |a HSP90 Heat-Shock Proteins: metabolism
|2 MeSH
650 _ 2 |a HSP90 Heat-Shock Proteins: toxicity
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Magnetic Resonance Spectroscopy
|2 MeSH
650 _ 2 |a Models, Molecular
|2 MeSH
650 _ 2 |a Phosphorylation: drug effects
|2 MeSH
650 _ 2 |a Protein Binding: drug effects
|2 MeSH
650 _ 2 |a Protein Conformation
|2 MeSH
650 _ 2 |a Tacrolimus Binding Proteins: chemistry
|2 MeSH
650 _ 2 |a Tacrolimus Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a Tacrolimus Binding Proteins: toxicity
|2 MeSH
650 _ 2 |a tau Proteins: chemistry
|2 MeSH
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
650 _ 2 |a tau Proteins: toxicity
|2 MeSH
700 1 _ |a Chang, Bliss J
|b 1
700 1 _ |a Wysoczanski, Piotr
|0 P:(DE-2719)2811216
|b 2
|u dzne
700 1 _ |a Lee, Chung-Tien
|b 3
700 1 _ |a Pérez-Lara, Ángel
|b 4
700 1 _ |a Chakraborty, Pijush
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700 1 _ |a Hofele, Romina V
|b 6
700 1 _ |a Baker, Jeremy D
|b 7
700 1 _ |a Blair, Laura J
|b 8
700 1 _ |a Biernat, Jacek
|0 P:(DE-2719)2810342
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700 1 _ |a Urlaub, Henning
|b 10
700 1 _ |a Mandelkow, Eckhard
|0 P:(DE-2719)2541671
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700 1 _ |a Dickey, Chad A
|b 12
700 1 _ |a Zweckstetter, Markus
|0 P:(DE-2719)2810591
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773 1 8 |a 10.1038/s41467-018-06880-0
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|t Nature Communications
|v 9
|y 2018
|x 2041-1723
773 _ _ |a 10.1038/s41467-018-06880-0
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|0 PERI:(DE-600)2553671-0
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856 4 _ |y OpenAccess
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856 7 _ |2 Pubmed Central
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