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

2019Journal article Open access
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dc.contributor.authorSaelices, L.
dc.contributor.authorNguyen, B.
dc.contributor.authorChung, K.
dc.contributor.authorWang, Y.
dc.contributor.authorOrtega, A.
dc.contributor.authorLee, J.
dc.contributor.authorCoelho, T.
dc.contributor.authorBijzet, J.
dc.contributor.authorBenson, M.
dc.contributor.authorEisenberg, D.
dc.date.accessioned2020-05-14T15:38:28Z
dc.date.available2020-05-14T15:38:28Z
dc.date.issued2019
dc.description.abstractThe 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.pt_PT
dc.description.sponsorshipThis work was supported by Amyloidosis Foundation Grant 20160759 and 20170827, National Institutes of Health Grant R01-AG048120, and The Howard Hughes Medical Institute. The authors and UCLA have filed an international patent application for the TTR inhibitors (number PCT/US17/40103). D. S. E. is an advisor and equity holder of ADRx, Inc. L. S. is a consultant of ADRx, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationSaelices L, Nguyen BA, Chung K, et al. A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils. J Biol Chem. 2019;294(15):6130‐6141. doi:10.1074/jbc.RA118.005257pt_PT
dc.identifier.doi10.1074/jbc.RA118.005257pt_PT
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttp://hdl.handle.net/10400.16/2392
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Society for Biochemistry and Molecular Biologypt_PT
dc.relationPCT/US17/40103pt_PT
dc.relation.publisherversionhttps://www.jbc.org/content/294/15/6130.longpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectagingpt_PT
dc.subjectamyloidpt_PT
dc.subjectamyloidosispt_PT
dc.subjectdrug discoverypt_PT
dc.subjectinhibitionpt_PT
dc.subjectinhibition mechanismpt_PT
dc.subjectpeptidept_PT
dc.subjectpeptidespt_PT
dc.subjectprotein aggregationpt_PT
dc.subjectseedingpt_PT
dc.subjecttransthyretinpt_PT
dc.titleA pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrilspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceUnited States of Americapt_PT
oaire.citation.endPage6141pt_PT
oaire.citation.issue15pt_PT
oaire.citation.startPage6130pt_PT
oaire.citation.titleThe Journal of biological chemistrypt_PT
oaire.citation.volume294pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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