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

Autores
Esperante, Sebastian; Varejao, Nathalia; Pinheiro, Francisca; Sant'Anna, Ricardo; Luque Ortega, Juan Román; Alfonso, Carlos; Sora, Valentina; Papaleo, Elena; Rivas, Germán; Reverter, David; Ventura, Salvador
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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 WTTTR, 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.
Fil: Esperante, Sebastian. Universitat Autònoma de Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Varejao, Nathalia. Universitat Autònoma de Barcelona; España
Fil: Pinheiro, Francisca. Universitat Autònoma de Barcelona; España
Fil: Sant'Anna, Ricardo. Universitat Autònoma de Barcelona; España
Fil: Luque Ortega, Juan Román. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España
Fil: Alfonso, Carlos. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España
Fil: Sora, Valentina. Technical University of Denmark; Dinamarca
Fil: Papaleo, Elena. Technical University of Denmark; Dinamarca
Fil: Rivas, Germán. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España
Fil: Reverter, David. Universitat Autònoma de Barcelona; España
Fil: Ventura, Salvador. Universitat Autònoma de Barcelona; España
Materia
TRANSTHYRETIN
AMYLOIDOSIS
MUTATIONS
AGGREGATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/147848
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/147848
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregationEsperante, SebastianVarejao, NathaliaPinheiro, FranciscaSant'Anna, RicardoLuque Ortega, Juan RománAlfonso, CarlosSora, ValentinaPapaleo, ElenaRivas, GermánReverter, DavidVentura, SalvadorTRANSTHYRETINAMYLOIDOSISMUTATIONSAGGREGATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Hereditary 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 WTTTR, 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.Fil: Esperante, Sebastian. Universitat Autònoma de Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Varejao, Nathalia. Universitat Autònoma de Barcelona; EspañaFil: Pinheiro, Francisca. Universitat Autònoma de Barcelona; EspañaFil: Sant'Anna, Ricardo. Universitat Autònoma de Barcelona; EspañaFil: Luque Ortega, Juan Román. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; EspañaFil: Alfonso, Carlos. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; EspañaFil: Sora, Valentina. Technical University of Denmark; DinamarcaFil: Papaleo, Elena. Technical University of Denmark; DinamarcaFil: Rivas, Germán. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; EspañaFil: Reverter, David. Universitat Autònoma de Barcelona; EspañaFil: Ventura, Salvador. Universitat Autònoma de Barcelona; EspañaAmerican Society for Biochemistry and Molecular Biology2021-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/147848Esperante, Sebastian; Varejao, Nathalia; Pinheiro, Francisca; Sant'Anna, Ricardo; Luque Ortega, Juan Román; et al.; Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 297; 3; 9-2021; 1-140021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.jbc.org/article/S0021-9258(21)00841-3/fulltextinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.jbc.2021.101039info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:29:59Zoai:ri.conicet.gov.ar:11336/147848instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:30:00.155CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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
AMYLOIDOSIS
MUTATIONS
AGGREGATION
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
Varejao, 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
Varejao, 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 Varejao, 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.subject.none.fl_str_mv TRANSTHYRETIN
AMYLOIDOSIS
MUTATIONS
AGGREGATION
topic TRANSTHYRETIN
AMYLOIDOSIS
MUTATIONS
AGGREGATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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 WTTTR, 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.
Fil: Esperante, Sebastian. Universitat Autònoma de Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Varejao, Nathalia. Universitat Autònoma de Barcelona; España
Fil: Pinheiro, Francisca. Universitat Autònoma de Barcelona; España
Fil: Sant'Anna, Ricardo. Universitat Autònoma de Barcelona; España
Fil: Luque Ortega, Juan Román. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España
Fil: Alfonso, Carlos. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España
Fil: Sora, Valentina. Technical University of Denmark; Dinamarca
Fil: Papaleo, Elena. Technical University of Denmark; Dinamarca
Fil: Rivas, Germán. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España
Fil: Reverter, David. Universitat Autònoma de Barcelona; España
Fil: Ventura, Salvador. Universitat Autònoma de Barcelona; España
description 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 WTTTR, 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.
publishDate 2021
dc.date.none.fl_str_mv 2021-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/147848
Esperante, Sebastian; Varejao, Nathalia; Pinheiro, Francisca; Sant'Anna, Ricardo; Luque Ortega, Juan Román; et al.; Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 297; 3; 9-2021; 1-14
0021-9258
CONICET Digital
CONICET
url http://hdl.handle.net/11336/147848
identifier_str_mv Esperante, Sebastian; Varejao, Nathalia; Pinheiro, Francisca; Sant'Anna, Ricardo; Luque Ortega, Juan Román; et al.; Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 297; 3; 9-2021; 1-14
0021-9258
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.jbc.org/article/S0021-9258(21)00841-3/fulltext
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jbc.2021.101039
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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