TY  - JOUR
AU  - Oroz, Javier
AU  - Kim, Jin Hae
AU  - Chang, Bliss J
AU  - Zweckstetter, Markus
TI  - Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90.
JO  - Nature structural & molecular biology
VL  - 24
IS  - 4
SN  - 1545-9993
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DZNE-2020-05500
SP  - 407-413
PY  - 2017
AB  - 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.
KW  - HSP90 Heat-Shock Proteins: chemistry
KW  - HSP90 Heat-Shock Proteins: metabolism
KW  - Humans
KW  - Imaging, Three-Dimensional
KW  - Intrinsically Disordered Proteins: chemistry
KW  - Intrinsically Disordered Proteins: metabolism
KW  - Magnetic Resonance Spectroscopy
KW  - Models, Biological
KW  - Models, Molecular
KW  - Molecular Chaperones: chemistry
KW  - Molecular Chaperones: metabolism
KW  - Prealbumin: chemistry
KW  - Prealbumin: metabolism
KW  - Protein Binding
KW  - Protein Conformation
KW  - Protein Folding
KW  - Protein Multimerization
KW  - tau Proteins: chemistry
KW  - tau Proteins: metabolism
KW  - HSP90 Heat-Shock Proteins (NLM Chemicals)
KW  - Intrinsically Disordered Proteins (NLM Chemicals)
KW  - Molecular Chaperones (NLM Chemicals)
KW  - Prealbumin (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28218749
DO  - DOI:10.1038/nsmb.3380
UR  - https://pub.dzne.de/record/139178
ER  -