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Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90

Nature Structural & Molecular Biology volume 24, pages 407413 (2017) | Download Citation

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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.

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Change history

  • 13 March 2017

    In the version of this article initially published online, there was an error in the y-axis label of Figure 1e. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank M. Mizuguchi (University of Toyama, Toyama, Japan) for the transthyretin plasmid; C.A. Dickey (University of South Florida, Tampa, Florida, USA) for the Hsp90 plasmid; and C.A. Dickey, B.A. Nordhues and S.G. Rüdiger for useful discussions. We are grateful to M. Ubbink (Leiden University, Leiden, the Netherlands) for the CLanP-7 lanthanide tag, to P. Wysoczanski for help with NMR spectroscopy experiments recorded for Hsp90's M domain, and to A. Pérez-Lara for help with ITC experiments. This work was supported by the Alexander von Humboldt Foundation (fellowship to J.H.K.), the European Commission (Marie Curie Intra-European fellowship, project number 626526 to J.O.), the Fulbright Program (scholarship to B.J.C.) and the European Community's Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant agreement 283570 to M.Z.).

Author information

Author notes

    • Javier Oroz
    •  & Jin Hae Kim

    These authors contributed equally to this work.

Affiliations

  1. German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

    • Javier Oroz
    • , Jin Hae Kim
    •  & Markus Zweckstetter
  2. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.

    • Bliss J Chang
    •  & Markus Zweckstetter
  3. Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany.

    • Markus Zweckstetter

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Contributions

J.H.K. performed NMR spectroscopy and biochemical experiments on TTR variants, as well as structure calculations. J.O. performed NMR spectroscopy, SAXS and ITC experiments on Hsp90. B.J.C. and J.O. produced Hsp90 mutants for the assignment of isoleucine methyl groups. J.H.K., J.O. and M.Z. designed experiments. J.H.K., J.O. and M.Z. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Markus Zweckstetter.

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https://doi.org/10.1038/nsmb.3380

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