Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer

Autores
Zanotti, Giuseppe; Vallese, Francesca; Ferrari, Alberto José; Menozzi, Ilaria; Saldaño, Tadeo Enrique; Berto, Paola; Fernández Alberti, Sebastián; Berni, Rodolfo
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The molecular symmetry of multimeric proteins is generally determined by using X-ray diffraction techniques, so that the basic question as to whether this symmetry is perfectly preserved for the same protein in solution remains open. In this work, human transthyretin (TTR), a homotetrameric plasma transport protein with two binding sites for the thyroid hormone thyroxine (T4), is considered as a case study. Based on the crystal structure of the TTR tetramer, a hypothetical D2 symmetry is inferred for the protein in solution, whose functional behavior reveals the presence of two markedly different Kd values for the two T4 binding sites. The latter property has been ascribed to an as yet uncharacterized negative binding cooperativity. A triple mutant form of human TTR (F87M/L110M/S117E TTR), which is monomeric in solution, crystallizes as a tetrameric protein and its structure has been determined. The exam of this and several other crystal forms of human TTR suggests that the TTR scaffold possesses a significant structural flexibility. In addition, TTR tetramer dynamics simulated using normal modes analysis exposes asymmetric vibrational patterns on both dimers and thermal fluctuations reveal small differences in size and flexibility for ligand cavities at each dimer-dimer interface. Such small structural differences between monomers can lead to significant functional differences on the TTR tetramer dynamics, a feature that may explain the functional heterogeneity of the T4 binding sites, which is partially overshadowed by the crystal state.
Fil: Zanotti, Giuseppe. Università di Padova; Italia
Fil: Vallese, Francesca. Università di Padova; Italia
Fil: Ferrari, Alberto José. Università di Parma; Italia
Fil: Menozzi, Ilaria. Università di Parma; Italia
Fil: Saldaño, Tadeo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Berto, Paola. Università di Padova; Italia
Fil: Fernández Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Berni, Rodolfo. Università di Parma; Italia
Materia
TRANSTHYRETIN
X-RAY
NORMAL MODES
STRUCTURAL FLEXIBILITY
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:11336/41474
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/41474
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramerZanotti, GiuseppeVallese, FrancescaFerrari, Alberto JoséMenozzi, IlariaSaldaño, Tadeo EnriqueBerto, PaolaFernández Alberti, SebastiánBerni, RodolfoTRANSTHYRETINX-RAYNORMAL MODESSTRUCTURAL FLEXIBILITYhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The molecular symmetry of multimeric proteins is generally determined by using X-ray diffraction techniques, so that the basic question as to whether this symmetry is perfectly preserved for the same protein in solution remains open. In this work, human transthyretin (TTR), a homotetrameric plasma transport protein with two binding sites for the thyroid hormone thyroxine (T4), is considered as a case study. Based on the crystal structure of the TTR tetramer, a hypothetical D2 symmetry is inferred for the protein in solution, whose functional behavior reveals the presence of two markedly different Kd values for the two T4 binding sites. The latter property has been ascribed to an as yet uncharacterized negative binding cooperativity. A triple mutant form of human TTR (F87M/L110M/S117E TTR), which is monomeric in solution, crystallizes as a tetrameric protein and its structure has been determined. The exam of this and several other crystal forms of human TTR suggests that the TTR scaffold possesses a significant structural flexibility. In addition, TTR tetramer dynamics simulated using normal modes analysis exposes asymmetric vibrational patterns on both dimers and thermal fluctuations reveal small differences in size and flexibility for ligand cavities at each dimer-dimer interface. Such small structural differences between monomers can lead to significant functional differences on the TTR tetramer dynamics, a feature that may explain the functional heterogeneity of the T4 binding sites, which is partially overshadowed by the crystal state.Fil: Zanotti, Giuseppe. Università di Padova; ItaliaFil: Vallese, Francesca. Università di Padova; ItaliaFil: Ferrari, Alberto José. Università di Parma; ItaliaFil: Menozzi, Ilaria. Università di Parma; ItaliaFil: Saldaño, Tadeo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Berto, Paola. Università di Padova; ItaliaFil: Fernández Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Berni, Rodolfo. Università di Parma; ItaliaPublic Library of Science2017-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/41474Zanotti, Giuseppe; Vallese, Francesca; Ferrari, Alberto José; Menozzi, Ilaria; Saldaño, Tadeo Enrique; et al.; Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer; Public Library of Science; Plos One; 12; 12; 12-20171932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0187716info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187716info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:36:24Zoai:ri.conicet.gov.ar:11336/41474instacron: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 09:36:24.66CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer
title Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer
spellingShingle Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer
Zanotti, Giuseppe
TRANSTHYRETIN
X-RAY
NORMAL MODES
STRUCTURAL FLEXIBILITY
title_short Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer
title_full Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer
title_fullStr Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer
title_full_unstemmed Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer
title_sort Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer
dc.creator.none.fl_str_mv Zanotti, Giuseppe
Vallese, Francesca
Ferrari, Alberto José
Menozzi, Ilaria
Saldaño, Tadeo Enrique
Berto, Paola
Fernández Alberti, Sebastián
Berni, Rodolfo
author Zanotti, Giuseppe
author_facet Zanotti, Giuseppe
Vallese, Francesca
Ferrari, Alberto José
Menozzi, Ilaria
Saldaño, Tadeo Enrique
Berto, Paola
Fernández Alberti, Sebastián
Berni, Rodolfo
author_role author
author2 Vallese, Francesca
Ferrari, Alberto José
Menozzi, Ilaria
Saldaño, Tadeo Enrique
Berto, Paola
Fernández Alberti, Sebastián
Berni, Rodolfo
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TRANSTHYRETIN
X-RAY
NORMAL MODES
STRUCTURAL FLEXIBILITY
topic TRANSTHYRETIN
X-RAY
NORMAL MODES
STRUCTURAL FLEXIBILITY
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The molecular symmetry of multimeric proteins is generally determined by using X-ray diffraction techniques, so that the basic question as to whether this symmetry is perfectly preserved for the same protein in solution remains open. In this work, human transthyretin (TTR), a homotetrameric plasma transport protein with two binding sites for the thyroid hormone thyroxine (T4), is considered as a case study. Based on the crystal structure of the TTR tetramer, a hypothetical D2 symmetry is inferred for the protein in solution, whose functional behavior reveals the presence of two markedly different Kd values for the two T4 binding sites. The latter property has been ascribed to an as yet uncharacterized negative binding cooperativity. A triple mutant form of human TTR (F87M/L110M/S117E TTR), which is monomeric in solution, crystallizes as a tetrameric protein and its structure has been determined. The exam of this and several other crystal forms of human TTR suggests that the TTR scaffold possesses a significant structural flexibility. In addition, TTR tetramer dynamics simulated using normal modes analysis exposes asymmetric vibrational patterns on both dimers and thermal fluctuations reveal small differences in size and flexibility for ligand cavities at each dimer-dimer interface. Such small structural differences between monomers can lead to significant functional differences on the TTR tetramer dynamics, a feature that may explain the functional heterogeneity of the T4 binding sites, which is partially overshadowed by the crystal state.
Fil: Zanotti, Giuseppe. Università di Padova; Italia
Fil: Vallese, Francesca. Università di Padova; Italia
Fil: Ferrari, Alberto José. Università di Parma; Italia
Fil: Menozzi, Ilaria. Università di Parma; Italia
Fil: Saldaño, Tadeo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Berto, Paola. Università di Padova; Italia
Fil: Fernández Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Berni, Rodolfo. Università di Parma; Italia
description The molecular symmetry of multimeric proteins is generally determined by using X-ray diffraction techniques, so that the basic question as to whether this symmetry is perfectly preserved for the same protein in solution remains open. In this work, human transthyretin (TTR), a homotetrameric plasma transport protein with two binding sites for the thyroid hormone thyroxine (T4), is considered as a case study. Based on the crystal structure of the TTR tetramer, a hypothetical D2 symmetry is inferred for the protein in solution, whose functional behavior reveals the presence of two markedly different Kd values for the two T4 binding sites. The latter property has been ascribed to an as yet uncharacterized negative binding cooperativity. A triple mutant form of human TTR (F87M/L110M/S117E TTR), which is monomeric in solution, crystallizes as a tetrameric protein and its structure has been determined. The exam of this and several other crystal forms of human TTR suggests that the TTR scaffold possesses a significant structural flexibility. In addition, TTR tetramer dynamics simulated using normal modes analysis exposes asymmetric vibrational patterns on both dimers and thermal fluctuations reveal small differences in size and flexibility for ligand cavities at each dimer-dimer interface. Such small structural differences between monomers can lead to significant functional differences on the TTR tetramer dynamics, a feature that may explain the functional heterogeneity of the T4 binding sites, which is partially overshadowed by the crystal state.
publishDate 2017
dc.date.none.fl_str_mv 2017-12
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/11336/41474
Zanotti, Giuseppe; Vallese, Francesca; Ferrari, Alberto José; Menozzi, Ilaria; Saldaño, Tadeo Enrique; et al.; Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer; Public Library of Science; Plos One; 12; 12; 12-2017
1932-6203
CONICET Digital
CONICET
url http://hdl.handle.net/11336/41474
identifier_str_mv Zanotti, Giuseppe; Vallese, Francesca; Ferrari, Alberto José; Menozzi, Ilaria; Saldaño, Tadeo Enrique; et al.; Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer; Public Library of Science; Plos One; 12; 12; 12-2017
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.0187716
info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187716
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
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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