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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/71960
Ver los metadatos del registro completo
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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 |
_version_ |
1844613761821835264 |
score |
13.070432 |