An engineered transthyretin monomer that is nonamyloidogenic, unless it is partially denatured. Three Turkish families with different transthyretin mutations. Tabulation of human transthyretin (TTR) variants, 2003. Transthyretin related familial amyloid polyneuropathy. Endoplasmic reticulum proteostasis influences the oligomeric state of an amyloidogenic protein secreted from mammalian cells. Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell. Hsp90-Tau complex reveals molecular basis for specificity in chaperone action. Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic β-cell. The molecular chaperone Hsp90 modulates intermediate steps of amyloid assembly of the Parkinson-related protein α-synuclein. Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. Substrate binding drives large-scale conformational changes in the Hsp90 molecular chaperone. Transient interaction of Hsp90 with early unfolding intermediates of citrate synthase. Pharmacologic shifting of a balance between protein refolding and degradation mediated by Hsp90. Polypeptide interactions with molecular chaperones and their relationship to in vivo protein folding. Proteostasis impairment in protein-misfolding and -aggregation diseases. Molecular chaperones and protein quality control. Roles of molecular chaperones in protein misfolding diseases. Protein misfolding, functional amyloid, and human disease. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. 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. 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. In the bound state, the Hsp90 dimer predominantly populates an open conformation, and transthyretin retains its globular structure. The misfolded transthyretin monomer, but not the wild-type protein, binds to human Hsp90. 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. Their interaction with molecular chaperones such as Hsp90, which preferentially interacts with metastable proteins, is essential for the blocking of disease progression. The critical toxic species in over 40 human diseases are misfolded proteins.
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