PDBsum entry 4xfn

Protein fibril

PDB id: 4xfn

Contents

Ligands

ALA-GLU-VAL-VAL-PHE-THR ×2

Waters ×6

PDB id:

4xfn

Name:

Protein fibril

Title:

Structure of an amyloid forming peptide aevvft from human transthyretin

Structure:

Amyloid forming peptide aevvft. Chain: a, b. Engineered: yes

Source:

Synthetic: yes. Synthetic construct. Organism_taxid: 32630. Other_details: this sequence corresponds to a segment of human transthyretin

Resolution:

1.85Å R-factor: 0.158 R-free: 0.201

Authors:

L.Saelices,M.Sawaya,D.Cascio,D.S.Eisenberg

Key ref:

L.Saelices et al. (2015). Uncovering the Mechanism of Aggregation of Human Transthyretin. J Biol Chem, 290, 28932-28943. PubMed id: 26459562 DOI: 10.1074/jbc.M115.659912

Date:

27-Dec-14 Release date: 21-Oct-15

DOI no: 10.1074/jbc.M115.659912

J Biol Chem 290:28932-28943 (2015)

PubMed id: 26459562

Uncovering the Mechanism of Aggregation of Human Transthyretin.

L.Saelices, L.M.Johnson, W.Y.Liang, M.R.Sawaya, D.Cascio, P.Ruchala, J.Whitelegge, L.Jiang, R.Riek, D.S.Eisenberg.

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.