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Uncovering the Mechanism of Aggregation of Human Transthyretin.

  • Saelices L From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570, Swiss Federal Institute of Technology in Zürich (ETH), Physical Chemistry, ETH Hönggerberg, 8093 Zürich, Switzerland, and.
  • Johnson LM From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
  • Liang WY From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
  • Sawaya MR From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
  • Cascio D From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
  • Ruchala P the Department of Psychiatry and Biobehavioral Sciences, UCLA and The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, Los Angeles, California 90024.
  • Whitelegge J the Department of Psychiatry and Biobehavioral Sciences, UCLA and The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, Los Angeles, California 90024.
  • Jiang L From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
  • Riek R Swiss Federal Institute of Technology in Zürich (ETH), Physical Chemistry, ETH Hönggerberg, 8093 Zürich, Switzerland, and.
  • Eisenberg DS From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570, david@mbi.ucla.edu.
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  • 2015-10-14
Published in:
  • The Journal of biological chemistry. - 2015
TTR
amyloid
inhibition mechanism
mutational analysis
peptide interaction
protein aggregation
transthyretin amyloidosis
x-ray crystallography
Amyloid
Amyloid Neuropathies, Familial
Humans
Models, Molecular
Peptides
Prealbumin
Protein Aggregates
Protein Structure, Secondary
English 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.
Language
  • English
Open access status
hybrid
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Persistent URL
https://sonar.ch/global/documents/41004
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