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      Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex

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          Abstract

          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.

          Abstract

          The chaperone Hsp90 plays a key role in maintaining cellular homeostasis. Here the authors provide structural insights into substrate recognition and the pro-folding mechanism of Hsp90/co-chaperone complexes by studying the complex of Hsp90 with its co-chaperone FKBP51 and the substrate Tau bound Hsp90/FKBP51 ternary complex using a NMR based integrative approach.

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          Most cited references59

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          Molecular chaperones in protein folding and proteostasis.

          Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
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            The HSP90 chaperone machinery

            The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis. Recent progress has shed light on the interactions of HSP90 with its clients and co-chaperones, and on their functional implications. This opens up new avenues for the development of drugs that target HSP90, which could be valuable for the treatment of cancers and protein-misfolding diseases.
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              Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex.

              Hsp90 (heat shock protein of 90 kDa) is a ubiquitous molecular chaperone responsible for the assembly and regulation of many eukaryotic signalling systems and is an emerging target for rational chemotherapy of many cancers. Although the structures of isolated domains of Hsp90 have been determined, the arrangement and ATP-dependent dynamics of these in the full Hsp90 dimer have been elusive and contentious. Here we present the crystal structure of full-length yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1. The structure reveals the complex architecture of the 'closed' state of the Hsp90 chaperone, the extensive interactions between domains and between protein chains, the detailed conformational changes in the amino-terminal domain that accompany ATP binding, and the structural basis for stabilization of the closed state by p23/Sba1. Contrary to expectations, the closed Hsp90 would not enclose its client proteins but provides a bipartite binding surface whose formation and disruption are coupled to the chaperone ATPase cycle.
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                Author and article information

                Contributors
                Markus.Zweckstetter@dzne.de
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                31 October 2018
                31 October 2018
                2018
                : 9
                : 4532
                Affiliations
                [1 ]ISNI 0000 0004 0438 0426, GRID grid.424247.3, German Center for Neurodegenerative Diseases (DZNE), ; Von-Siebold-Straße 3a, 37075 Göttingen, Germany
                [2 ]ISNI 0000 0001 2104 4211, GRID grid.418140.8, Department for NMR-based Structural Biology, , Max Planck Institute for Biophysical Chemistry, ; Am Faßberg 11, 37077 Göttingen, Germany
                [3 ]ISNI 0000 0001 2104 4211, GRID grid.418140.8, Bioanalytical Mass Spectrometry, , Max Planck Institute for Biophysical Chemistry, ; Am Faßberg 11, 37077 Göttingen, Germany
                [4 ]ISNI 0000 0001 2104 4211, GRID grid.418140.8, Department of Neurobiology, , Max Planck Institute for Biophysical Chemistry, ; Am Faßberg 11, 37077 Göttingen, Germany
                [5 ]ISNI 0000 0001 2353 285X, GRID grid.170693.a, Department of Molecular Medicine, Morsani College of Medicine, USF Health Byrd Alzheimer’s Institute, , University of South Florida, ; Tampa, FL 33613 USA
                [6 ]ISNI 0000 0004 0438 0426, GRID grid.424247.3, DZNE, CAESAR Research Center, ; Ludwig-Erhard-Alle 2, 53175 Bonn, Germany
                [7 ]ISNI 0000 0001 0482 5331, GRID grid.411984.1, Bioanalytics Group, Institute for Clinical Chemistry, , University Medical Center, ; Robert-Koch-Straße 40, 37075 Göttingen, Germany
                [8 ]Present Address: Instituto de Química-Física Rocasolano, IQFR-CSIC, Serrano 119, 28006 Madrid, Spain
                Author information
                http://orcid.org/0000-0002-4551-0499
                http://orcid.org/0000-0002-2736-3501
                http://orcid.org/0000-0002-4981-5564
                http://orcid.org/0000-0003-3834-3159
                http://orcid.org/0000-0002-2536-6581
                Article
                6880
                10.1038/s41467-018-06880-0
                6208366
                30382094
                504f14b5-45d0-4a0c-89ce-992ae3026f73
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 31 May 2018
                : 3 October 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000781, EC | European Research Council (ERC);
                Award ID: 787679 - LLPS-NMR
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Award ID: SFB860/B2
                Award ID: SFB860/A10
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: R01 NS073899
                Award ID: R01 MH103848
                Award Recipient :
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