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Title: Uncovering the mechanism of aggregation of human transthyretin

Journal Article · · Journal of Biological Chemistry
 [1];  [2];  [2];  [2];  [2];  [3];  [3];  [2];  [4];  [2]
  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)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE; Howard Hughes Medical Institute
Grant/Contract Number:
AC02-06CH11357; FC02-02ER63421; AG04812; AG029430; 8 P41 GM103403-10
OSTI ID:
1228108
Journal Information:
Journal of Biological Chemistry, Vol. 290, Issue 48; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 97 works
Citation information provided by
Web of Science

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Cited By (25)

Amyloid-Polymorphie in der Energielandschaft der Faltung und Aggregation von Proteinen journal June 2018
Peptid‐basierte molekulare Strategien zum Einsatz bei Proteinfehlfaltung, Proteinaggregation und Zelldegeneration journal November 2019
Amyloid Polymorphism in the Protein Folding and Aggregation Energy Landscape journal June 2018
Peptide‐Based Molecular Strategies To Interfere with Protein Misfolding, Aggregation, and Cell Degeneration journal November 2019
Crystallographic insights into the self‐assembly of KLVFF amyloid‐beta peptides journal February 2018
Crystal structures of amyloidogenic segments of human transthyretin: Amyloid Structures of Transthyretin Segments journal June 2018
Inhibition of protein misfolding and aggregation by natural phenolic compounds journal July 2018
The activities of amyloids from a structural perspective journal November 2016
Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2 journal March 2018
Development of transgenic Caenorhabditis elegans expressing human transthyretin as a model for drug screening journal December 2018
Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers journal January 2019
Fundamentals of cross-seeding of amyloid proteins: an introduction journal January 2019
Specific keratinase derived designer peptides potently inhibit Aβ aggregation resulting in reduced neuronal toxicity and apoptosis journal June 2019
A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils journal February 2019
A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH journal June 2019
Protein aggregation, misfolding and consequential human neurodegenerative diseases journal February 2017
Emerging therapeutic targets currently under investigation for the treatment of systemic amyloidosis journal October 2017
Treatment of cardiac transthyretin amyloidosis: an update journal May 2019
The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin journal March 2020
Amyloid fibril polymorphism: a challenge for molecular imaging and therapy journal February 2018
Distinct C9orf72-Associated Dipeptide Repeat Structures Correlate with Neuronal Toxicity journal October 2016
Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin journal March 2016
Exploration of the Misfolding Mechanism of Transthyretin Monomer: Insights from Hybrid-Resolution Simulations and Markov State Model Analysis journal December 2019
Structure-based inhibitors of amyloid beta core suggest a common interface with tau journal October 2019
Peptid-basierte molekulare Strategien zum Einsatz bei Proteinfehlfaltung, Proteinaggregation und Zelldegeneration text January 2019

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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