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Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity

2020-12-03Journal article Open access
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dc.contributor.authorFrangolho, Ana
dc.contributor.authorCorreia, Bruno E.
dc.contributor.authorVaz, Daniela C.
dc.contributor.authorAlmeida, Zaida L.
dc.contributor.authorBrito, Rui M. M.
dc.date.accessioned2020-12-16T14:35:28Z
dc.date.available2020-12-16T14:35:28Z
dc.date.issued2020-12-03
dc.description.abstractOne of the molecular hallmarks of amyloidoses is ordered protein aggregation involving the initial formation of soluble protein oligomers that eventually grow into insoluble fibrils. The identification and characterization of molecular species critical for amyloid fibril formation and disease development have been the focus of intense analysis in the literature. Here, using photo-induced cross-linking of unmodified proteins (PICUP), we studied the early stages of oligomerization of human transthyretin (TTR), a plasma protein involved in amyloid diseases (ATTR amyloidosis) with multiple clinical manifestations. Upon comparison, the oligomerization processes of wild-type TTR (TTRwt) and several TTR variants (TTRV30M, TTRL55P, and TTRT119M) clearly show distinct oligomerization kinetics for the amyloidogenic variants but a similar oligomerization mechanism. The oligomerization kinetics of the TTR amyloidogenic variants under analysis showed a good correlation with their amyloidogenic potential, with the most amyloidogenic variants aggregating faster (TTRL55P > TTRV30M > TTRwt). Moreover, the early stage oligomerization mechanism for these variants involves stepwise addition of monomeric units to the growing oligomer. A completely different behavior was observed for the nonamyloidogenic TTRT119M variant, which does not form oligomers in the same acidic conditions and even for longer incubation times. Thorough characterization of the initial steps of TTR oligomerization is critical for better understanding the origin of ATTR cytotoxicity and developing novel therapeutic strategies for the treatment of ATTR amyloidosis.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.3390/molecules25235698pt_PT
dc.identifier.issn1420-3049
dc.identifier.urihttp://hdl.handle.net/10400.8/5230
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationUIDB/QUI/00313/2020pt_PT
dc.relationUIDP/QUI/00313/2020pt_PT
dc.subjectTransthyretinpt_PT
dc.subjectTTRpt_PT
dc.subjectTTR variantspt_PT
dc.subjectAmyloidosispt_PT
dc.subjectATTRpt_PT
dc.subjectLinear oligomerizationpt_PT
dc.subjectDownhill polymerizationpt_PT
dc.subjectAggregationpt_PT
dc.subjectAmyloidpt_PT
dc.titleOligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage14pt_PT
oaire.citation.startPage1pt_PT
oaire.citation.titleMoleculespt_PT
oaire.citation.volume25pt_PT
person.familyNameBarroso de Moura Cipreste Vaz
person.familyNameAlmeida
person.familyNameBrito
person.givenNameDaniela
person.givenNameZaida L.
person.givenNameRui
person.identifier932298
person.identifier.ciencia-id801A-7761-328C
person.identifier.ciencia-id8E19-C3BB-2B00
person.identifier.orcid0000-0001-7562-4676
person.identifier.orcid0000-0002-4097-2766
person.identifier.orcid0000-0001-9128-2557
person.identifier.ridR-5243-2017
person.identifier.scopus-author-id6602838931
person.identifier.scopus-author-id7005511461
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication518f12af-3297-4334-b00b-c06e17b2cf27
relation.isAuthorOfPublicationfd4669ec-bb00-4f25-82f8-20c6d6d104fc
relation.isAuthorOfPublication7685eb09-0505-40c1-9849-661f1f8f144b
relation.isAuthorOfPublication.latestForDiscoveryfd4669ec-bb00-4f25-82f8-20c6d6d104fc

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