Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation

14 p.-7 fig.-2 tab.

Detalles Bibliográficos
Autores: Esperante, Sebastian, Varejão, Nathalia, Pinheiro, Francisca, Sant’Anna, Ricardo, Luque-Ortega, Juan Román, Alfonso, Carlos, Sora, Valentina, Papaleo, Elena, Rivas, Germán, Reverter, David, Ventura, Salvador
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/251330
Acceso en línea:http://hdl.handle.net/10261/251330
Access Level:acceso abierto
Palabra clave:Transthyretin
Amyloid
Aggregation
Protein structure
Protein stability
Molecular dynamics
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spelling Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregationEsperante, SebastianVarejão, NathaliaPinheiro, FranciscaSant’Anna, RicardoLuque-Ortega, Juan RománAlfonso, CarlosSora, ValentinaPapaleo, ElenaRivas, GermánReverter, DavidVentura, SalvadorTransthyretinAmyloidAggregationProtein structureProtein stabilityMolecular dynamics14 p.-7 fig.-2 tab.Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by the extracellular deposition of the transport protein transthyretin (TTR) as amyloid fibrils. Despite the progress achieved in recent years, understanding why different TTR residue substitutions lead to different clinical manifestations remains elusive. Here, we studied the molecular basis of disease-causing missense mutations affecting residues R34 and K35. R34G and K35T variants cause vitreous amyloidosis, whereas R34T and K35N mutations result in amyloid polyneuropathy and restrictive cardiomyopathy. All variants are more sensitive to pH-induced dissociation and amyloid formation than the wild-type (WT)-TTR counterpart, specifically in the variants deposited in the eyes amyloid formation occurs close to physiological pHs. Chemical denaturation experiments indicate that all the mutants are less stable than WT-TTR, with the vitreous amyloidosis variants, R34G and K35T, being highly destabilized. Sequence-induced stabilization of the dimer–dimer interface with T119M rendered tetramers containing R34G or K35T mutations resistant to pH-induced aggregation. Because R34 and K35 are among the residues more distant to the TTR interface, their impact in this region is therefore theorized to occur at long range. The crystal structures of double mutants, R34G/T119M and K35T/T119M, together with molecular dynamics simulations indicate that their strong destabilizing effect is initiated locally at the BC loop, increasing its flexibility in a mutation-dependent manner. Overall, the present findings help us to understand the sequence-dynamic-structural mechanistic details of TTR amyloid aggregation triggered by R34 and K35 variants and to link the degree of mutation-induced conformational flexibility to protein aggregation propensity.This work was funded by the Spanish Ministry of Science and Innovation PID2019-105017RB-100 to S. V., PID2019-104544GB-I00 to C. A., and by ICREA, ICREA-Academia 2020 to S. V. and Danmarks Grundforskningsfond (DNRF125) and Carlsbergfondet Distinguished Fellowship (CF18-0314) to E. P.Peer reviewedElsevierMinisterio de Ciencia e Innovación (España)Institución Catalana de Investigación y Estudios AvanzadosDanish National Research FoundationCarlsberg FoundationEsperante, Sebastian [0000-0002-5778-6871]Varejão, Nathalia [0000-0002-6952-8896]Pinheiro, Francisca [0000-0003-3778-1528]Luque-Ortega, Juan Román [0000-0003-3206-7480]Alfonso, Carlos [0000-0001-7165-4800]Sora, Valentina [0000-0002-6969-8174]Papaleo, Elena [0000-0002-7376-5894]Rivas, Germán [0000-0003-3450-7478]Reverter, David [0000-0002-5347-0992]Ventura, Salvador [0000-0002-9652-6351]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/251330reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105017RB-100info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104544GB-I00https://doi.org/10.1016/j.jbc.2021.101039Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2513302026-05-22T06:33:51Z
dc.title.none.fl_str_mv Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation
title Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation
spellingShingle Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation
Esperante, Sebastian
Transthyretin
Amyloid
Aggregation
Protein structure
Protein stability
Molecular dynamics
title_short Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation
title_full Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation
title_fullStr Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation
title_full_unstemmed Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation
title_sort Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation
dc.creator.none.fl_str_mv Esperante, Sebastian
Varejão, Nathalia
Pinheiro, Francisca
Sant’Anna, Ricardo
Luque-Ortega, Juan Román
Alfonso, Carlos
Sora, Valentina
Papaleo, Elena
Rivas, Germán
Reverter, David
Ventura, Salvador
author Esperante, Sebastian
author_facet Esperante, Sebastian
Varejão, Nathalia
Pinheiro, Francisca
Sant’Anna, Ricardo
Luque-Ortega, Juan Román
Alfonso, Carlos
Sora, Valentina
Papaleo, Elena
Rivas, Germán
Reverter, David
Ventura, Salvador
author_role author
author2 Varejão, Nathalia
Pinheiro, Francisca
Sant’Anna, Ricardo
Luque-Ortega, Juan Román
Alfonso, Carlos
Sora, Valentina
Papaleo, Elena
Rivas, Germán
Reverter, David
Ventura, Salvador
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Institución Catalana de Investigación y Estudios Avanzados
Danish National Research Foundation
Carlsberg Foundation
Esperante, Sebastian [0000-0002-5778-6871]
Varejão, Nathalia [0000-0002-6952-8896]
Pinheiro, Francisca [0000-0003-3778-1528]
Luque-Ortega, Juan Román [0000-0003-3206-7480]
Alfonso, Carlos [0000-0001-7165-4800]
Sora, Valentina [0000-0002-6969-8174]
Papaleo, Elena [0000-0002-7376-5894]
Rivas, Germán [0000-0003-3450-7478]
Reverter, David [0000-0002-5347-0992]
Ventura, Salvador [0000-0002-9652-6351]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Transthyretin
Amyloid
Aggregation
Protein structure
Protein stability
Molecular dynamics
topic Transthyretin
Amyloid
Aggregation
Protein structure
Protein stability
Molecular dynamics
description 14 p.-7 fig.-2 tab.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/251330
url http://hdl.handle.net/10261/251330
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105017RB-100
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104544GB-I00
https://doi.org/10.1016/j.jbc.2021.101039
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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