Uncovering the mechanism of aggregation of human transthyretin

Lorena Saelices, Lisa M. Johnson, Wilson Y. Liang, Michael R. Sawaya, Duilio Cascio, Piotr Ruchala, Julian Whitelegge, Lin Jiang, Roland Riek, David S. Eisenberg

Research output: Contribution to journalArticlepeer-review

107 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)28932-28943
Number of pages12
JournalJournal of Biological Chemistry
Issue number48
StatePublished - Nov 27 2015

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© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


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