title: Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90.
abstract: The critical toxic species in over 40 human diseases are misfolded proteins. Their interaction with molecular chaperones such as Hsp90, which preferentially interacts with metastable proteins, is essential for the blocking of disease progression. Here we used nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structure of the misfolded cytotoxic monomer of the amyloidogenic human protein transthyretin, which is characterized by the release of the C-terminal β-strand and perturbations of the A-B loop. The misfolded transthyretin monomer, but not the wild-type protein, binds to human Hsp90. In the bound state, the Hsp90 dimer predominantly populates an open conformation, and transthyretin retains its globular structure. The interaction surface for the transthyretin monomer comprises the N-terminal and middle domains of Hsp90 and overlaps with that of the Alzheimer's-disease-related protein tau. Taken together, the data suggest that Hsp90 uses a mechanism for the recognition of aggregation-prone proteins that is largely distinct from those of other Hsp90 clients.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Oroz
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
authors.forename: Jin Hae
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Bliss J
authors.identifier: 0000-0002-4551-0499
authors.initials: BJ
authors.lastname: Chang
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.|Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany.
authors.forename: Markus
authors.identifier: 0000-0002-2536-6581
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D021621:Imaging, Three-Dimensional; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism*; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D064267:Intrinsically Disordered Proteins; D018832:Molecular Chaperones; D011228:Prealbumin; D016875:tau Proteins