4XFN

Structure of an Amyloid forming peptide AEVVFT from Human Transthyretin

Summary for 4XFN

• Entry DOI: 10.2210/pdb4xfn/pdb
• Related: 4XFO
• Descriptor: Amyloid forming peptide AEVVFT (2 entities in total)
• Functional Keywords: amyloid, transthyretin, fibril, protein fibril
• Biological source: synthetic construct
• Total number of polymer chains: 2
• Total formula weight: 1329.49

Authors

Saelices, L.,Sawaya, M.,Cascio, D.,Eisenberg, D.S. (deposition date: 2014-12-27, release date: 2015-10-21, Last modification date: 2024-02-28)

Primary citation

Saelices, L.,Johnson, L.M.,Liang, W.Y.,Sawaya, M.R.,Cascio, D.,Ruchala, P.,Whitelegge, J.,Jiang, L.,Riek, R.,Eisenberg, D.S.
Uncovering the Mechanism of Aggregation of Human Transthyretin.
J.Biol.Chem., 290:28932-28943, 2015

PubMed 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.

PubMed: 26459562
DOI: 10.1074/jbc.M115.659912

Experimental method

X-RAY DIFFRACTION (1.85 Å)