title: Uncovering the Mechanism of Aggregation of Human Transthyretin.
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.
authors.affiliation: 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.
authors.forename: Lorena
authors.initials: L
authors.lastname: Saelices
authors.affiliation: From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Johnson
authors.affiliation: From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
authors.forename: Wilson Y
authors.initials: WY
authors.lastname: Liang
authors.affiliation: From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sawaya
authors.affiliation: From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
authors.forename: Duilio
authors.initials: D
authors.lastname: Cascio
authors.affiliation: 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.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruchala
authors.affiliation: 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.
authors.forename: Julian
authors.initials: J
authors.lastname: Whitelegge
authors.affiliation: From the Department of Biological Chemistry, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095-1570.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Swiss Federal Institute of Technology in Zürich (ETH), Physical Chemistry, ETH Hönggerberg, 8093 Zürich, Switzerland, and.
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Eisenberg
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011228:Prealbumin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D010455:Peptides; D011228:Prealbumin; D066329:Protein Aggregates
keywords: TTR; amyloid; inhibition mechanism; mutational analysis; peptide interaction; protein aggregation; transthyretin amyloidosis; x-ray crystallography