Uncovering the Mechanism of Aggregation of Human Transthyretin
Copyright policy )Uncovering the Mechanism of Aggregation of Human Transthyretin
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.
Journal of Biological Chemistry, 290 (48)
ISSN:0021-9258
ISSN:1083-351X
- ETH Zurich Switzerland
- University of California, San Francisco United States
- École Polytechnique Fédérale de Lausanne EPFL Switzerland
- Semel Institute for Neuroscience and Human Behavior United States
- University of California, Los Angeles United States
Models, Molecular, Aging, Secondary, Biomedical and clinical sciences, Amyloid; Inhibition mechanism; Peptide interaction; Protein aggregation; X-ray crystallography; Mutational analysis; TTR; Transthyretin amyloidosis, Neurodegenerative, Alzheimer's Disease, Amyloid Neuropathies, Medical and Health Sciences, Protein Structure, Secondary, Transthyretin amyloidosis, Familial, Models, 2.1 Biological and endogenous factors, Prealbumin, Inhibition mechanism, Aetiology, amyloid, Molecular Bases of Disease, Biological Sciences, Biological sciences, Peptide interaction, 5.1 Pharmaceuticals, inhibition mechanism, Development of treatments and therapeutic interventions, Protein aggregation, mutational analysis, 570, Protein Structure, Biochemistry & Molecular Biology, Amyloid, TTR, peptide interaction, protein aggregation, Protein Aggregates, Rare Diseases, Acquired Cognitive Impairment, Humans, x-ray crystallography, X-ray crystallography, Amyloid Neuropathies, Familial, Biomedical and Clinical Sciences, transthyretin amyloidosis, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Molecular, Mutational analysis, Brain Disorders, Orphan Drug, Chemical sciences, Chemical Sciences, Dementia, Biochemistry and Cell Biology, Peptides
Models, Molecular, Aging, Secondary, Biomedical and clinical sciences, Amyloid; Inhibition mechanism; Peptide interaction; Protein aggregation; X-ray crystallography; Mutational analysis; TTR; Transthyretin amyloidosis, Neurodegenerative, Alzheimer's Disease, Amyloid Neuropathies, Medical and Health Sciences, Protein Structure, Secondary, Transthyretin amyloidosis, Familial, Models, 2.1 Biological and endogenous factors, Prealbumin, Inhibition mechanism, Aetiology, amyloid, Molecular Bases of Disease, Biological Sciences, Biological sciences, Peptide interaction, 5.1 Pharmaceuticals, inhibition mechanism, Development of treatments and therapeutic interventions, Protein aggregation, mutational analysis, 570, Protein Structure, Biochemistry & Molecular Biology, Amyloid, TTR, peptide interaction, protein aggregation, Protein Aggregates, Rare Diseases, Acquired Cognitive Impairment, Humans, x-ray crystallography, X-ray crystallography, Amyloid Neuropathies, Familial, Biomedical and Clinical Sciences, transthyretin amyloidosis, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Molecular, Mutational analysis, Brain Disorders, Orphan Drug, Chemical sciences, Chemical Sciences, Dementia, Biochemistry and Cell Biology, Peptides
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