Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein

Autores
Rodriguez-Granillo, Agustina; Crespo, Alejandro; Estrin, Dario Ariel; Wittung-Stafshede, Pernilla
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metalbinding domains (MBDs) of P1B-type ATPases are still unclear. Here, we use a computational approach, employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light on the reaction mechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics] of Cu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 have solvent-exposed metal-binding motifs with two Cys residues that coordinate Cu(I). After assessing the existence of all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First, without activation barrier, WD4's Cys1 binds Cu(I) in Atox1 to form a 3-coordinated intermediate. Next, with an activation barrier of about 9.5 kcal/mol, a second 3-coordinated intermediate forms that involves both of the Cys residues in WD4 and Cys1 of Atox1. This species can then form the product by decoordination of Atox1's Cys1 (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appears to be kinetically accessible but less energetically favorable (△E = 7.7 kcal/mol). Our results provide unique insights into the molecular mechanism of protein-mediated Cu(I) transfer in the secretory pathway and are in agreement with existing experimental data. © 2010 American Chemical Society.
Fil: Rodriguez-Granillo, Agustina. Rice Universite; Estados Unidos
Fil: Crespo, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Rice Universite; Estados Unidos. Merck Research Laboratories; Estados Unidos
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Wittung-Stafshede, Pernilla. Rice University; Estados Unidos. Universidad de Umea; Suecia
Materia
Chaperon
Atox1
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:11336/71960

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network_name_str CONICET Digital (CONICET)
spelling Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease proteinRodriguez-Granillo, AgustinaCrespo, AlejandroEstrin, Dario ArielWittung-Stafshede, PernillaChaperonAtox1https://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metalbinding domains (MBDs) of P1B-type ATPases are still unclear. Here, we use a computational approach, employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light on the reaction mechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics] of Cu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 have solvent-exposed metal-binding motifs with two Cys residues that coordinate Cu(I). After assessing the existence of all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First, without activation barrier, WD4's Cys1 binds Cu(I) in Atox1 to form a 3-coordinated intermediate. Next, with an activation barrier of about 9.5 kcal/mol, a second 3-coordinated intermediate forms that involves both of the Cys residues in WD4 and Cys1 of Atox1. This species can then form the product by decoordination of Atox1's Cys1 (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appears to be kinetically accessible but less energetically favorable (△E = 7.7 kcal/mol). Our results provide unique insights into the molecular mechanism of protein-mediated Cu(I) transfer in the secretory pathway and are in agreement with existing experimental data. © 2010 American Chemical Society.Fil: Rodriguez-Granillo, Agustina. Rice Universite; Estados UnidosFil: Crespo, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Rice Universite; Estados Unidos. Merck Research Laboratories; Estados UnidosFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Wittung-Stafshede, Pernilla. Rice University; Estados Unidos. Universidad de Umea; SueciaAmerican Chemical Society2010-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/71960Rodriguez-Granillo, Agustina; Crespo, Alejandro; Estrin, Dario Ariel; Wittung-Stafshede, Pernilla; Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein; American Chemical Society; Journal of Physical Chemistry B; 114; 10; 3-2010; 3698-37061520-6106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/abs/10.1021/jp911208zinfo:eu-repo/semantics/altIdentifier/doi/10.1021/jp911208zinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:59:21Zoai:ri.conicet.gov.ar:11336/71960instacron: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 09:59:21.919CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein
title Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein
spellingShingle Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein
Rodriguez-Granillo, Agustina
Chaperon
Atox1
title_short Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein
title_full Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein
title_fullStr Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein
title_full_unstemmed Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein
title_sort Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein
dc.creator.none.fl_str_mv Rodriguez-Granillo, Agustina
Crespo, Alejandro
Estrin, Dario Ariel
Wittung-Stafshede, Pernilla
author Rodriguez-Granillo, Agustina
author_facet Rodriguez-Granillo, Agustina
Crespo, Alejandro
Estrin, Dario Ariel
Wittung-Stafshede, Pernilla
author_role author
author2 Crespo, Alejandro
Estrin, Dario Ariel
Wittung-Stafshede, Pernilla
author2_role author
author
author
dc.subject.none.fl_str_mv Chaperon
Atox1
topic Chaperon
Atox1
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metalbinding domains (MBDs) of P1B-type ATPases are still unclear. Here, we use a computational approach, employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light on the reaction mechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics] of Cu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 have solvent-exposed metal-binding motifs with two Cys residues that coordinate Cu(I). After assessing the existence of all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First, without activation barrier, WD4's Cys1 binds Cu(I) in Atox1 to form a 3-coordinated intermediate. Next, with an activation barrier of about 9.5 kcal/mol, a second 3-coordinated intermediate forms that involves both of the Cys residues in WD4 and Cys1 of Atox1. This species can then form the product by decoordination of Atox1's Cys1 (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appears to be kinetically accessible but less energetically favorable (△E = 7.7 kcal/mol). Our results provide unique insights into the molecular mechanism of protein-mediated Cu(I) transfer in the secretory pathway and are in agreement with existing experimental data. © 2010 American Chemical Society.
Fil: Rodriguez-Granillo, Agustina. Rice Universite; Estados Unidos
Fil: Crespo, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Rice Universite; Estados Unidos. Merck Research Laboratories; Estados Unidos
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Wittung-Stafshede, Pernilla. Rice University; Estados Unidos. Universidad de Umea; Suecia
description The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metalbinding domains (MBDs) of P1B-type ATPases are still unclear. Here, we use a computational approach, employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light on the reaction mechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics] of Cu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 have solvent-exposed metal-binding motifs with two Cys residues that coordinate Cu(I). After assessing the existence of all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First, without activation barrier, WD4's Cys1 binds Cu(I) in Atox1 to form a 3-coordinated intermediate. Next, with an activation barrier of about 9.5 kcal/mol, a second 3-coordinated intermediate forms that involves both of the Cys residues in WD4 and Cys1 of Atox1. This species can then form the product by decoordination of Atox1's Cys1 (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appears to be kinetically accessible but less energetically favorable (△E = 7.7 kcal/mol). Our results provide unique insights into the molecular mechanism of protein-mediated Cu(I) transfer in the secretory pathway and are in agreement with existing experimental data. © 2010 American Chemical Society.
publishDate 2010
dc.date.none.fl_str_mv 2010-03
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/11336/71960
Rodriguez-Granillo, Agustina; Crespo, Alejandro; Estrin, Dario Ariel; Wittung-Stafshede, Pernilla; Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein; American Chemical Society; Journal of Physical Chemistry B; 114; 10; 3-2010; 3698-3706
1520-6106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/71960
identifier_str_mv Rodriguez-Granillo, Agustina; Crespo, Alejandro; Estrin, Dario Ariel; Wittung-Stafshede, Pernilla; Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of wilson disease protein; American Chemical Society; Journal of Physical Chemistry B; 114; 10; 3-2010; 3698-3706
1520-6106
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://pubs.acs.org/doi/abs/10.1021/jp911208z
info:eu-repo/semantics/altIdentifier/doi/10.1021/jp911208z
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 Chemical Society
publisher.none.fl_str_mv American Chemical Society
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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