Uncovering the mechanism of aggregation of human transthyretin [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 536.2 Heat transfer
• Thông tin xuất bản: Bethesda, Md. : Oak Ridge, Tenn. : National Institutes of Health (U.S.) ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015
• Mô tả vật lý: Size: p. 28932-28943 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261047
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 59 basic biological sciences; 3. 60 applied life sciences; 4. Amyloid; 5. Et al; 6. Inhibition mechanism; 7. Mutational analysis; 8. Peptide interaction; 9. Protein aggregation; 10. Ttr; 11. X-ray crystallography

Tóm tắt

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 ?-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. Lastly, this work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy.