2NBO

Solution structure of the F87M/L110M variant of transthyretin in the monomeric state

Summary for 2NBO

• Entry DOI: 10.2210/pdb2nbo/pdb
• Related: 2NBP
• NMR Information: BMRB: 25986
• Descriptor: Transthyretin (1 entity in total)
• Functional Keywords: transthyretin, amyloid, aggregation, misfolded, monomer, transport protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 1
• Total formula weight: 13779.42

Authors

Kim, J.,Oroz, J.,Zweckstetter, M. (deposition date: 2016-03-09, release date: 2017-02-22, Last modification date: 2024-05-15)

Primary citation

Oroz, J.,Kim, J.H.,Chang, B.J.,Zweckstetter, M.
Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90.
Nat. Struct. Mol. Biol., 24:407-413, 2017

PubMed 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.

PubMed: 28218749
DOI: 10.1038/nsmb.3380

Experimental method

SOLUTION NMR