Abstract
The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of transthyretin has been reported as the cause of the life-threatening transthyretin amyloidosis. The standard treatment of familial cases of TTR amyloidosis has been liver transplantation. Although aggregation-preventing strategies involving ligands are known, understanding the mechanism of TTR aggregation can lead to additional inhibition approaches. Several models of TTR amyloid fibrils have been proposed, but the segments that drive aggregation of the protein have remained unknown. Here we identify β-strands F and H as necessary for TTR aggregation. Based on the crystal structures of these segments, we designed two non-natural peptide inhibitors that block aggregation. This work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000108864Publication status
publishedExternal links
Journal / series
Journal of Biological ChemistryVolume
Pages / Article No.
Publisher
The American Society for Biochemistry and Molecular BiologySubject
Amyloid; Inhibition mechanism; Peptide interaction; Protein aggregation; X-ray crystallography; Mutational analysis; TTR; Transthyretin amyloidosisOrganisational unit
03782 - Riek, Roland / Riek, Roland
Notes
Published online 12 October 2015.More
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ETH Bibliography
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