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A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils

Saelices, L., Nguyen, B. A., Chung, K., Wang, Y., Ortega, A., Lee, J. H., Coelho, T., Bijzet, J., Benson, M. D. & Eisenberg, D. S., 12-Apr-2019, In : Journal of Biological Chemistry. 294, 15, p. 6130-6141 12 p.

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  • A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils

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DOI

  • Lorena Saelices
  • Binh A. Nguyen
  • Kevin Chung
  • Yifei Wang
  • Alfredo Ortega
  • Ji H. Lee
  • Teresa Coelho
  • Johan Bijzet
  • Merrill D. Benson
  • David S. Eisenberg

The tetrameric protein transthyretin is a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, and is secreted by the liver, choroid plexus, and retinal epithelium, respectively. Systemic amyloid deposition of aggregated transthyretin causes hereditary and sporadic amyloidoses. A common treatment of patients with hereditary transthyretin amyloidosis is liver transplantation. However, this procedure, which replaces the patient's variant transthyretin with the WT protein, can fail to stop subsequent cardiac deposition, ultimately requiring heart transplantation. We recently showed that preformed amyloid fibrils present in the heart at the time of surgery can template or seed further amyloid aggregation of native transthyretin. Here we assess possible interventions to halt this seeding, using biochemical and EM assays. We found that chemical or mutational stabilization of the transthyretin tetramer does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex vivo fibrils efficiently inhibits amyloid seeding by impeding self-association of the amyloid-driving strands F and H in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach.

Original languageEnglish
Pages (from-to)6130-6141
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number15
Publication statusPublished - 12-Apr-2019

    Keywords

  • amyloid, protein aggregation, inhibition mechanism, aging, drug discovery, peptides, amyloidosis, inhibition, peptide, seeding, transthyretin, TAFAMIDIS, POLYNEUROPATHY, PROTEIN, AGGREGATION, DIFLUNISAL, DEPOSITS, SAFETY, POTENT

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