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000140308 041__ $$aEnglish
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000140308 1001_ $$0P:(DE-2719)2810826$$aOroz, Javier$$b0$$eFirst author$$udzne
000140308 245__ $$aStructure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex.
000140308 260__ $$a[London]$$bNature Publishing Group UK$$c2018
000140308 264_1 $$2Crossref$$3online$$bSpringer Science and Business Media LLC$$c2018-10-31
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000140308 520__ $$aThe molecular chaperone Hsp90 is critical for the maintenance of cellular homeostasis and represents a promising drug target. Despite increasing knowledge on the structure of Hsp90, the molecular basis of substrate recognition and pro-folding by Hsp90/co-chaperone complexes remains unknown. Here, we report the solution structures of human full-length Hsp90 in complex with the PPIase FKBP51, as well as the 280 kDa Hsp90/FKBP51 complex bound to the Alzheimer's disease-related protein Tau. We reveal that the FKBP51/Hsp90 complex, which synergizes to promote toxic Tau oligomers in vivo, is highly dynamic and stabilizes the extended conformation of the Hsp90 dimer resulting in decreased Hsp90 ATPase activity. Within the ternary Hsp90/FKBP51/Tau complex, Hsp90 serves as a scaffold that traps the PPIase and nucleates multiple conformations of Tau's proline-rich region next to the PPIase catalytic pocket in a phosphorylation-dependent manner. Our study defines a conceptual model for dynamic Hsp90/co-chaperone/client recognition.
000140308 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000140308 542__ $$2Crossref$$i2018-10-31$$uhttps://creativecommons.org/licenses/by/4.0
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000140308 650_7 $$2NLM Chemicals$$aHSP90 Heat-Shock Proteins
000140308 650_7 $$2NLM Chemicals$$atau Proteins
000140308 650_7 $$0EC 5.2.1.-$$2NLM Chemicals$$aTacrolimus Binding Proteins
000140308 650_7 $$0EC 5.2.1.8$$2NLM Chemicals$$atacrolimus binding protein 5
000140308 650_2 $$2MeSH$$aBiocatalysis: drug effects
000140308 650_2 $$2MeSH$$aHSP90 Heat-Shock Proteins: chemistry
000140308 650_2 $$2MeSH$$aHSP90 Heat-Shock Proteins: metabolism
000140308 650_2 $$2MeSH$$aHSP90 Heat-Shock Proteins: toxicity
000140308 650_2 $$2MeSH$$aHumans
000140308 650_2 $$2MeSH$$aMagnetic Resonance Spectroscopy
000140308 650_2 $$2MeSH$$aModels, Molecular
000140308 650_2 $$2MeSH$$aPhosphorylation: drug effects
000140308 650_2 $$2MeSH$$aProtein Binding: drug effects
000140308 650_2 $$2MeSH$$aProtein Conformation
000140308 650_2 $$2MeSH$$aTacrolimus Binding Proteins: chemistry
000140308 650_2 $$2MeSH$$aTacrolimus Binding Proteins: metabolism
000140308 650_2 $$2MeSH$$aTacrolimus Binding Proteins: toxicity
000140308 650_2 $$2MeSH$$atau Proteins: chemistry
000140308 650_2 $$2MeSH$$atau Proteins: metabolism
000140308 650_2 $$2MeSH$$atau Proteins: toxicity
000140308 7001_ $$aChang, Bliss J$$b1
000140308 7001_ $$0P:(DE-2719)2811216$$aWysoczanski, Piotr$$b2$$udzne
000140308 7001_ $$aLee, Chung-Tien$$b3
000140308 7001_ $$aPérez-Lara, Ángel$$b4
000140308 7001_ $$0P:(DE-2719)2812532$$aChakraborty, Pijush$$b5$$udzne
000140308 7001_ $$aHofele, Romina V$$b6
000140308 7001_ $$aBaker, Jeremy D$$b7
000140308 7001_ $$aBlair, Laura J$$b8
000140308 7001_ $$0P:(DE-2719)2810342$$aBiernat, Jacek$$b9$$udzne
000140308 7001_ $$aUrlaub, Henning$$b10
000140308 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b11$$udzne
000140308 7001_ $$aDickey, Chad A$$b12
000140308 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b13$$eLast author$$udzne
000140308 77318 $$2Crossref$$3journal-article$$a10.1038/s41467-018-06880-0$$b : Springer Science and Business Media LLC, 2018-10-31$$n1$$p4532$$tNature Communications$$v9$$x2041-1723$$y2018
000140308 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-018-06880-0$$gVol. 9, no. 1, p. 4532$$n1$$p4532$$q9:1<4532$$tNature Communications$$v9$$x2041-1723$$y2018
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000140308 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208366
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