Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics

Autores
Saldaño, Tadeo Enrique; Zanotti, Giuseppe; Parisi, Gustavo Daniel; Fernández Alberti, Sebastián
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Native transthyretin (TTR) homotetramer dissociation is the first step of the fibrils formation process in amyloid disease. A large number of specific point mutations that destabilize TTR quaternary structure have shown pro-amyloidogenic effects. Besides, several compounds have been proposed as drugs in the therapy of TTR amyloidosis due to their TTR tetramer binding affinities, and therefore, contribution to its integrity. In the present paper we have explored key positions sustaining TTR tetramer dynamical stability. We have identified positions whose mutations alter the most the TTR tetramer equilibrium dynamics based on normal mode analysis and their response to local perturbations. We have found that these positions are mostly localized at β-strands E and F and EF-loop. The monomer-monomer interface is pointed out as one of the most vulnerable regions to mutations that lead to significant changes in the TTR-tetramer equilibrium dynamics and, therefore, induces TTR amyloidosis.Besides, we have found that mutations on residues localized at the dimer-dimerinterface and/or at the T4 hormone binding site destabilize the tetramer more than the average.Finally, we were able to compare several compounds according to their effect on vibrationsassociated to the ligand binding. Our ligand comparison is discussed and analyzed interms of parameters and measurements associated to TTR-ligand binding affinities and thestabilization of its native state.
Fil: Saldaño, Tadeo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Zanotti, Giuseppe. Università di Padova; Italia
Fil: Parisi, Gustavo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Fernández Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Materia
NORMAL MODES
EFFECT OF MUTATIONS
AMYLOIDOSIS
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:11336/41180
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/41180
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamicsSaldaño, Tadeo EnriqueZanotti, GiuseppeParisi, Gustavo DanielFernández Alberti, SebastiánNORMAL MODESEFFECT OF MUTATIONSAMYLOIDOSISNative transthyretin (TTR) homotetramer dissociation is the first step of the fibrils formation process in amyloid disease. A large number of specific point mutations that destabilize TTR quaternary structure have shown pro-amyloidogenic effects. Besides, several compounds have been proposed as drugs in the therapy of TTR amyloidosis due to their TTR tetramer binding affinities, and therefore, contribution to its integrity. In the present paper we have explored key positions sustaining TTR tetramer dynamical stability. We have identified positions whose mutations alter the most the TTR tetramer equilibrium dynamics based on normal mode analysis and their response to local perturbations. We have found that these positions are mostly localized at β-strands E and F and EF-loop. The monomer-monomer interface is pointed out as one of the most vulnerable regions to mutations that lead to significant changes in the TTR-tetramer equilibrium dynamics and, therefore, induces TTR amyloidosis.Besides, we have found that mutations on residues localized at the dimer-dimerinterface and/or at the T4 hormone binding site destabilize the tetramer more than the average.Finally, we were able to compare several compounds according to their effect on vibrationsassociated to the ligand binding. Our ligand comparison is discussed and analyzed interms of parameters and measurements associated to TTR-ligand binding affinities and thestabilization of its native state.Fil: Saldaño, Tadeo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Zanotti, Giuseppe. Università di Padova; ItaliaFil: Parisi, Gustavo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Fernández Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaPublic Library of Science2017-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/41180Saldaño, Tadeo Enrique; Zanotti, Giuseppe; Parisi, Gustavo Daniel; Fernández Alberti, Sebastián; Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics; Public Library of Science; Plos One; 12; 7; 7-20171932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0181019info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181019info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:55:48Zoai:ri.conicet.gov.ar:11336/41180instacron: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 09:55:48.901CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics
title Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics
spellingShingle Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics
Saldaño, Tadeo Enrique
NORMAL MODES
EFFECT OF MUTATIONS
AMYLOIDOSIS
title_short Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics
title_full Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics
title_fullStr Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics
title_full_unstemmed Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics
title_sort Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics
dc.creator.none.fl_str_mv Saldaño, Tadeo Enrique
Zanotti, Giuseppe
Parisi, Gustavo Daniel
Fernández Alberti, Sebastián
author Saldaño, Tadeo Enrique
author_facet Saldaño, Tadeo Enrique
Zanotti, Giuseppe
Parisi, Gustavo Daniel
Fernández Alberti, Sebastián
author_role author
author2 Zanotti, Giuseppe
Parisi, Gustavo Daniel
Fernández Alberti, Sebastián
author2_role author
author
author
dc.subject.none.fl_str_mv NORMAL MODES
EFFECT OF MUTATIONS
AMYLOIDOSIS
topic NORMAL MODES
EFFECT OF MUTATIONS
AMYLOIDOSIS
dc.description.none.fl_txt_mv Native transthyretin (TTR) homotetramer dissociation is the first step of the fibrils formation process in amyloid disease. A large number of specific point mutations that destabilize TTR quaternary structure have shown pro-amyloidogenic effects. Besides, several compounds have been proposed as drugs in the therapy of TTR amyloidosis due to their TTR tetramer binding affinities, and therefore, contribution to its integrity. In the present paper we have explored key positions sustaining TTR tetramer dynamical stability. We have identified positions whose mutations alter the most the TTR tetramer equilibrium dynamics based on normal mode analysis and their response to local perturbations. We have found that these positions are mostly localized at β-strands E and F and EF-loop. The monomer-monomer interface is pointed out as one of the most vulnerable regions to mutations that lead to significant changes in the TTR-tetramer equilibrium dynamics and, therefore, induces TTR amyloidosis.Besides, we have found that mutations on residues localized at the dimer-dimerinterface and/or at the T4 hormone binding site destabilize the tetramer more than the average.Finally, we were able to compare several compounds according to their effect on vibrationsassociated to the ligand binding. Our ligand comparison is discussed and analyzed interms of parameters and measurements associated to TTR-ligand binding affinities and thestabilization of its native state.
Fil: Saldaño, Tadeo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Zanotti, Giuseppe. Università di Padova; Italia
Fil: Parisi, Gustavo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Fernández Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
description Native transthyretin (TTR) homotetramer dissociation is the first step of the fibrils formation process in amyloid disease. A large number of specific point mutations that destabilize TTR quaternary structure have shown pro-amyloidogenic effects. Besides, several compounds have been proposed as drugs in the therapy of TTR amyloidosis due to their TTR tetramer binding affinities, and therefore, contribution to its integrity. In the present paper we have explored key positions sustaining TTR tetramer dynamical stability. We have identified positions whose mutations alter the most the TTR tetramer equilibrium dynamics based on normal mode analysis and their response to local perturbations. We have found that these positions are mostly localized at β-strands E and F and EF-loop. The monomer-monomer interface is pointed out as one of the most vulnerable regions to mutations that lead to significant changes in the TTR-tetramer equilibrium dynamics and, therefore, induces TTR amyloidosis.Besides, we have found that mutations on residues localized at the dimer-dimerinterface and/or at the T4 hormone binding site destabilize the tetramer more than the average.Finally, we were able to compare several compounds according to their effect on vibrationsassociated to the ligand binding. Our ligand comparison is discussed and analyzed interms of parameters and measurements associated to TTR-ligand binding affinities and thestabilization of its native state.
publishDate 2017
dc.date.none.fl_str_mv 2017-07
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/11336/41180
Saldaño, Tadeo Enrique; Zanotti, Giuseppe; Parisi, Gustavo Daniel; Fernández Alberti, Sebastián; Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics; Public Library of Science; Plos One; 12; 7; 7-2017
1932-6203
CONICET Digital
CONICET
url http://hdl.handle.net/11336/41180
identifier_str_mv Saldaño, Tadeo Enrique; Zanotti, Giuseppe; Parisi, Gustavo Daniel; Fernández Alberti, Sebastián; Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics; Public Library of Science; Plos One; 12; 7; 7-2017
1932-6203
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0181019
info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181019
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
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
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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