The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/10216/127409 |
Resumo: | Amyloid-β (Aβ) aggregation and neuroinflammation are consistent features in Alzheimer’s disease (AD) and strong candidates for the initiation of neurodegeneration. S100B is one of the most abundant proinflammatory proteins that is chronically up-regulated in AD and is found associated with senile plaques. This recognized bio-marker for brain distress may, thus, play roles in amyloid aggregation which remain to be determined. We report a novel role for the neuronal S100B protein as suppressor of A42 aggregation and toxicity. We determined the structural details of the interaction between monomeric A42 and S100B, which is favored by calcium binding to S100B, possibly involving conformational switching of disordered A42 into an -helical conformer, which locks aggregation. From nuclear magnetic resonance experiments, we show that this dynamic interaction occurs at a promiscuous peptide-binding region within the interfacial cleft of the S100B homodimer. This physical interaction is coupled to a functional role in the inhibition of A42 aggregation and toxicity and is tuned by calcium binding to S100B. S100B delays the onset of A42 aggregation by interacting with A42 monomers inhibiting primary nucleation, and the calcium-bound state substantially affects secondary nucleation by inhibiting fibril surface–catalyzed reactions through S100B binding to growing A42 oligomers and fibrils. S100B protects cells from A42-mediated toxicity, rescuing cell viability and decreasing apoptosis induced by A42 in cell cultures. Together, our findings suggest that molecular targeting of S100B could be translated into development of novel approaches to ameliorate AD neurodegeneration. |
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The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregationAmyloid-β (Aβ) aggregation and neuroinflammation are consistent features in Alzheimer’s disease (AD) and strong candidates for the initiation of neurodegeneration. S100B is one of the most abundant proinflammatory proteins that is chronically up-regulated in AD and is found associated with senile plaques. This recognized bio-marker for brain distress may, thus, play roles in amyloid aggregation which remain to be determined. We report a novel role for the neuronal S100B protein as suppressor of A42 aggregation and toxicity. We determined the structural details of the interaction between monomeric A42 and S100B, which is favored by calcium binding to S100B, possibly involving conformational switching of disordered A42 into an -helical conformer, which locks aggregation. From nuclear magnetic resonance experiments, we show that this dynamic interaction occurs at a promiscuous peptide-binding region within the interfacial cleft of the S100B homodimer. This physical interaction is coupled to a functional role in the inhibition of A42 aggregation and toxicity and is tuned by calcium binding to S100B. S100B delays the onset of A42 aggregation by interacting with A42 monomers inhibiting primary nucleation, and the calcium-bound state substantially affects secondary nucleation by inhibiting fibril surface–catalyzed reactions through S100B binding to growing A42 oligomers and fibrils. S100B protects cells from A42-mediated toxicity, rescuing cell viability and decreasing apoptosis induced by A42 in cell cultures. Together, our findings suggest that molecular targeting of S100B could be translated into development of novel approaches to ameliorate AD neurodegeneration.American Association for the Advancement of Science20182018-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10216/127409eng2375-254810.1126/sciadv.aaq1702Cristóvão, JMorris, VCardoso, ILeal, SMartínez, JBotelho, HGöbl, CDavid, RKierdorf, KAlemi, MMadl, TFritz, GReif, BGomes, Cinfo: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:RCAAP2023-11-29T15:10:03Zoai:repositorio-aberto.up.pt:10216/127409Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:17:14.382468Repositório 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 |
The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation |
title |
The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation |
spellingShingle |
The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation Cristóvão, J |
title_short |
The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation |
title_full |
The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation |
title_fullStr |
The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation |
title_full_unstemmed |
The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation |
title_sort |
The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation |
author |
Cristóvão, J |
author_facet |
Cristóvão, J Morris, V Cardoso, I Leal, S Martínez, J Botelho, H Göbl, C David, R Kierdorf, K Alemi, M Madl, T Fritz, G Reif, B Gomes, C |
author_role |
author |
author2 |
Morris, V Cardoso, I Leal, S Martínez, J Botelho, H Göbl, C David, R Kierdorf, K Alemi, M Madl, T Fritz, G Reif, B Gomes, C |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Cristóvão, J Morris, V Cardoso, I Leal, S Martínez, J Botelho, H Göbl, C David, R Kierdorf, K Alemi, M Madl, T Fritz, G Reif, B Gomes, C |
description |
Amyloid-β (Aβ) aggregation and neuroinflammation are consistent features in Alzheimer’s disease (AD) and strong candidates for the initiation of neurodegeneration. S100B is one of the most abundant proinflammatory proteins that is chronically up-regulated in AD and is found associated with senile plaques. This recognized bio-marker for brain distress may, thus, play roles in amyloid aggregation which remain to be determined. We report a novel role for the neuronal S100B protein as suppressor of A42 aggregation and toxicity. We determined the structural details of the interaction between monomeric A42 and S100B, which is favored by calcium binding to S100B, possibly involving conformational switching of disordered A42 into an -helical conformer, which locks aggregation. From nuclear magnetic resonance experiments, we show that this dynamic interaction occurs at a promiscuous peptide-binding region within the interfacial cleft of the S100B homodimer. This physical interaction is coupled to a functional role in the inhibition of A42 aggregation and toxicity and is tuned by calcium binding to S100B. S100B delays the onset of A42 aggregation by interacting with A42 monomers inhibiting primary nucleation, and the calcium-bound state substantially affects secondary nucleation by inhibiting fibril surface–catalyzed reactions through S100B binding to growing A42 oligomers and fibrils. S100B protects cells from A42-mediated toxicity, rescuing cell viability and decreasing apoptosis induced by A42 in cell cultures. Together, our findings suggest that molecular targeting of S100B could be translated into development of novel approaches to ameliorate AD neurodegeneration. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018 2018-01-01T00:00:00Z |
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 |
https://hdl.handle.net/10216/127409 |
url |
https://hdl.handle.net/10216/127409 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2375-2548 10.1126/sciadv.aaq1702 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
American Association for the Advancement of Science |
publisher.none.fl_str_mv |
American Association for the Advancement of Science |
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 |
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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 |
repository.mail.fl_str_mv |
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1799136092521234432 |