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

Authors:
 [1];  [2];  [2];  [2];  [2];  [3];  [3];  [2];  [4];  [2]
+ Show Author Affiliations
  1. Univ. of California, Los Angeles, CA (United States); Swiss Federal Institute of Technology in Zurich (ETH), Zurich (Switzerland)
  2. Univ. of California, Los Angeles, CA (United States)
  3. The Jane and Terry Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA (United States)
  4. Swiss Federal Institute of Technology in Zurich (ETH), Zurich (Switzerland)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE; Howard Hughes Medical Institute
OSTI Identifier:
1228108
Grant/Contract Number:  
AC02-06CH11357; FC02-02ER63421; AG04812; AG029430; 8 P41 GM103403-10
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 48; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; amyloid; inhibition mechanism; peptide interaction; protein aggregation; x-ray crystallography; mutational analysis; TTR; transthyretin amyloidosis

Citation Formats

Saelices, Lorena, Johnson, Lisa M., Liang, Wilson Y., Sawaya, Michael R., Cascio, Duilio, Ruchala, Piotr, Whitelegge, Julian, Jiang, Lin, Riek, Roland, and Eisenberg, David S. Uncovering the mechanism of aggregation of human transthyretin. United States: N. p., 2015. Web. doi:10.1074/jbc.M115.659912.
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Saelices, Lorena, Johnson, Lisa M., Liang, Wilson Y., Sawaya, Michael R., Cascio, Duilio, Ruchala, Piotr, Whitelegge, Julian, Jiang, Lin, Riek, Roland, & Eisenberg, David S. Uncovering the mechanism of aggregation of human transthyretin. United States. doi:https://doi.org/10.1074/jbc.M115.659912
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Saelices, Lorena, Johnson, Lisa M., Liang, Wilson Y., Sawaya, Michael R., Cascio, Duilio, Ruchala, Piotr, Whitelegge, Julian, Jiang, Lin, Riek, Roland, and Eisenberg, David S. Mon . "Uncovering the mechanism of aggregation of human transthyretin". United States. doi:https://doi.org/10.1074/jbc.M115.659912. https://www.osti.gov/servlets/purl/1228108.
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@article{osti_1228108,
title = {Uncovering the mechanism of aggregation of human transthyretin},
author = {Saelices, Lorena and Johnson, Lisa M. and Liang, Wilson Y. and Sawaya, Michael R. and Cascio, Duilio and Ruchala, Piotr and Whitelegge, Julian and Jiang, Lin and Riek, Roland and Eisenberg, David S.},
abstractNote = {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. Lastly, this work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy.},
doi = {10.1074/jbc.M115.659912},
journal = {Journal of Biological Chemistry},
number = 48,
volume = 290,
place = {United States},
year = {2015},
month = {10}
}
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DOI:  https://doi.org/10.1074/jbc.M115.659912
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