Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity

Detalhes bibliográficos
Autor(a) principal: Frangolho, Ana
Data de Publicação: 2020
Outros Autores: Correia, Bruno E., Vaz, Daniela C., Almeida, Zaida L., Brito, Rui M. M.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/106475
https://doi.org/10.3390/molecules25235698
Resumo: One 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.
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spelling Oligomerization Profile of Human Transthyretin Variants with Distinct AmyloidogenicitytransthyretinTTRTTR variantsamyloidosisATTRlinear oligomerizationdownhill polymerizationaggregationamyloidAmyloidAmyloidosisBlood ProteinsEscherichia coliHumansKineticsPolymerizationPrealbuminProtein AggregatesRecombinant ProteinsOne 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.MDPI2020-12-03info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/106475http://hdl.handle.net/10316/106475https://doi.org/10.3390/molecules25235698eng1420-3049Frangolho, AnaCorreia, Bruno E.Vaz, Daniela C.Almeida, Zaida L.Brito, Rui M. M.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-04-04T20:37:38Zoai:estudogeral.uc.pt:10316/106475Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:22:55.511473Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
title Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
spellingShingle Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
Frangolho, Ana
transthyretin
TTR
TTR variants
amyloidosis
ATTR
linear oligomerization
downhill polymerization
aggregation
amyloid
Amyloid
Amyloidosis
Blood Proteins
Escherichia coli
Humans
Kinetics
Polymerization
Prealbumin
Protein Aggregates
Recombinant Proteins
title_short Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
title_full Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
title_fullStr Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
title_full_unstemmed Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
title_sort Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
author Frangolho, Ana
author_facet Frangolho, Ana
Correia, Bruno E.
Vaz, Daniela C.
Almeida, Zaida L.
Brito, Rui M. M.
author_role author
author2 Correia, Bruno E.
Vaz, Daniela C.
Almeida, Zaida L.
Brito, Rui M. M.
author2_role author
author
author
author
dc.contributor.author.fl_str_mv Frangolho, Ana
Correia, Bruno E.
Vaz, Daniela C.
Almeida, Zaida L.
Brito, Rui M. M.
dc.subject.por.fl_str_mv transthyretin
TTR
TTR variants
amyloidosis
ATTR
linear oligomerization
downhill polymerization
aggregation
amyloid
Amyloid
Amyloidosis
Blood Proteins
Escherichia coli
Humans
Kinetics
Polymerization
Prealbumin
Protein Aggregates
Recombinant Proteins
topic transthyretin
TTR
TTR variants
amyloidosis
ATTR
linear oligomerization
downhill polymerization
aggregation
amyloid
Amyloid
Amyloidosis
Blood Proteins
Escherichia coli
Humans
Kinetics
Polymerization
Prealbumin
Protein Aggregates
Recombinant Proteins
description One 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.
publishDate 2020
dc.date.none.fl_str_mv 2020-12-03
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/106475
http://hdl.handle.net/10316/106475
https://doi.org/10.3390/molecules25235698
url http://hdl.handle.net/10316/106475
https://doi.org/10.3390/molecules25235698
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1420-3049
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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