title: Hsp90-Tau complex reveals molecular basis for specificity in chaperone action.
abstract: Protein folding in the cell relies on the orchestrated action of conserved families of molecular chaperones, the Hsp70 and Hsp90 systems. Hsp70 acts early and Hsp90 late in the folding path, yet the molecular basis of this timing is enigmatic, mainly because the substrate specificity of Hsp90 is poorly understood. Here, we obtained a structural model of Hsp90 in complex with its natural disease-associated substrate, the intrinsically disordered Tau protein. Hsp90 binds to a broad region in Tau that includes the aggregation-prone repeats. Complementarily, a 106-Å-long substrate-binding interface in Hsp90 enables many low-affinity contacts. This allows recognition of scattered hydrophobic residues in late folding intermediates that remain after early burial of the Hsp70 sites. Our model resolves the paradox of how Hsp90 specifically selects for late folding intermediates but also for some intrinsically disordered proteins-through the eyes of Hsp90 they look the same.
authors.affiliation: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
authors.forename: G Elif
authors.initials: GE
authors.lastname: Karagöz
authors.affiliation: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República EAN, 2780-157 Oeiras, Portugal.
authors.forename: Afonso M S
authors.initials: AM
authors.lastname: Duarte
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Elias
authors.initials: E
authors.lastname: Akoury
authors.affiliation: Biomolecular NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; CARIM School for Cardiovascular Diseases, Biochemistry Group, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Ippel
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.affiliation: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Tania
authors.initials: T
authors.lastname: Morán Luengo
authors.affiliation: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Martina
authors.initials: M
authors.lastname: Radli
authors.affiliation: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Didenko
authors.affiliation: Department of Pharmaceutical Sciences and Department of Molecular Medicine, University of South Florida Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Nordhues
authors.affiliation: Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland and Department of Biology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Dmitry B
authors.initials: DB
authors.lastname: Veprintsev
authors.affiliation: Department of Pharmaceutical Sciences and Department of Molecular Medicine, University of South Florida Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany; CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany; Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center, 37073 Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: Biomolecular NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Rolf
authors.initials: R
authors.lastname: Boelens
authors.affiliation: Biomolecular NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Institute of Structural Biology, Helmholtz Zentrum München Neuherberg and Biomolecular NMR-Spectroscopy, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany; Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria. Electronic address: t.madl@tum.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Madl
authors.affiliation: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. Electronic address: s.g.d.rudiger@uu.nl.
authors.forename: Stefan G D
authors.initials: SG
authors.lastname: Rüdiger
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000595:Amino Acid Sequence; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D016875:tau Proteins