Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115

Autores
Arcos López, Trinidad; Qayyum, Munzarin; Rivillas Acevedo, Lina; Miotto, Marco César; Grande Aztatzi, Rafael; Fernandez, Claudio Oscar; Hedman, Britt; Hodgson, Keith O.; Vela, Alberto; Solomon, Edward I.; Quintanar, Liliana
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The ability of the cellular prion protein (PrPC) to bind copper in vivo points to a physiological role for PrPC in copper transport. Six copper binding sites have been identified in the nonstructured N-terminal region of human PrPC. Among these sites, the His111 site is unique in that it contains a MKHM motif that would confer interesting CuI and CuII binding properties. We have evaluated CuI coordination to the PrP(106-115) fragment of the human PrP protein, using NMR and X-ray absorption spectroscopies and electronic structure calculations. We find that Met109 and Met112 play an important role in anchoring this metal ion. CuI coordination to His111 is pH-dependent: at pH >8, 2N1O1S species are formed with one Met ligand; in the range of pH 5-8, both methionine (Met) residues bind to CuI, forming a 1N1O2S species, where N is from His111 and O is from a backbone carbonyl or a water molecule; at pH <5, only the two Met residues remain coordinated. Thus, even upon drastic changes in the chemical environment, such as those occurring during endocytosis of PrPC (decreased pH and a reducing potential), the two Met residues in the MKHM motif enable PrPC to maintain the bound CuI ions, consistent with a copper transport function for this protein. We also find that the physiologically relevant CuI-1N1O2S species activates dioxygen via an inner-sphere mechanism, likely involving the formation of a copper(II) superoxide complex. In this process, the Met residues are partially oxidized to sulfoxide; this ability to scavenge superoxide may play a role in the proposed antioxidant properties of PrPC. This study provides further insight into the CuI coordination properties of His111 in human PrPC and the molecular mechanism of oxygen activation by this site.
Fil: Arcos López, Trinidad. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Fil: Qayyum, Munzarin. University of Stanford; Estados Unidos
Fil: Rivillas Acevedo, Lina. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Fil: Miotto, Marco César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Max Planck Laboratory for Structural Biology; Argentina
Fil: Grande Aztatzi, Rafael. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Max Planck Laboratory for Structural Biology; Argentina
Fil: Hedman, Britt. University of Stanford; Estados Unidos
Fil: Hodgson, Keith O.. University of Stanford; Estados Unidos
Fil: Vela, Alberto. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Fil: Solomon, Edward I.. University of Stanford; Estados Unidos
Fil: Quintanar, Liliana. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Materia
Cu(I)
Prion Protein
Biophysics
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:11336/52826
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/52826
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115Arcos López, TrinidadQayyum, MunzarinRivillas Acevedo, LinaMiotto, Marco CésarGrande Aztatzi, RafaelFernandez, Claudio OscarHedman, BrittHodgson, Keith O.Vela, AlbertoSolomon, Edward I.Quintanar, LilianaCu(I)Prion ProteinBiophysicshttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The ability of the cellular prion protein (PrPC) to bind copper in vivo points to a physiological role for PrPC in copper transport. Six copper binding sites have been identified in the nonstructured N-terminal region of human PrPC. Among these sites, the His111 site is unique in that it contains a MKHM motif that would confer interesting CuI and CuII binding properties. We have evaluated CuI coordination to the PrP(106-115) fragment of the human PrP protein, using NMR and X-ray absorption spectroscopies and electronic structure calculations. We find that Met109 and Met112 play an important role in anchoring this metal ion. CuI coordination to His111 is pH-dependent: at pH >8, 2N1O1S species are formed with one Met ligand; in the range of pH 5-8, both methionine (Met) residues bind to CuI, forming a 1N1O2S species, where N is from His111 and O is from a backbone carbonyl or a water molecule; at pH <5, only the two Met residues remain coordinated. Thus, even upon drastic changes in the chemical environment, such as those occurring during endocytosis of PrPC (decreased pH and a reducing potential), the two Met residues in the MKHM motif enable PrPC to maintain the bound CuI ions, consistent with a copper transport function for this protein. We also find that the physiologically relevant CuI-1N1O2S species activates dioxygen via an inner-sphere mechanism, likely involving the formation of a copper(II) superoxide complex. In this process, the Met residues are partially oxidized to sulfoxide; this ability to scavenge superoxide may play a role in the proposed antioxidant properties of PrPC. This study provides further insight into the CuI coordination properties of His111 in human PrPC and the molecular mechanism of oxygen activation by this site.Fil: Arcos López, Trinidad. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoFil: Qayyum, Munzarin. University of Stanford; Estados UnidosFil: Rivillas Acevedo, Lina. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoFil: Miotto, Marco César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Max Planck Laboratory for Structural Biology; ArgentinaFil: Grande Aztatzi, Rafael. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoFil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Max Planck Laboratory for Structural Biology; ArgentinaFil: Hedman, Britt. University of Stanford; Estados UnidosFil: Hodgson, Keith O.. University of Stanford; Estados UnidosFil: Vela, Alberto. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoFil: Solomon, Edward I.. University of Stanford; Estados UnidosFil: Quintanar, Liliana. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoAmerican Chemical Society2016-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/52826Arcos López, Trinidad; Qayyum, Munzarin; Rivillas Acevedo, Lina; Miotto, Marco César; Grande Aztatzi, Rafael; et al.; Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115; American Chemical Society; Inorganic Chemistry; 55; 6; 3-2016; 2909-29220020-1669CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/acs.inorgchem.5b02794info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.inorgchem.5b02794info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:02:45Zoai:ri.conicet.gov.ar:11336/52826instacron: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:34982025-10-22 11:02:45.519CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115
title Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115
spellingShingle Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115
Arcos López, Trinidad
Cu(I)
Prion Protein
Biophysics
title_short Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115
title_full Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115
title_fullStr Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115
title_full_unstemmed Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115
title_sort Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115
dc.creator.none.fl_str_mv Arcos López, Trinidad
Qayyum, Munzarin
Rivillas Acevedo, Lina
Miotto, Marco César
Grande Aztatzi, Rafael
Fernandez, Claudio Oscar
Hedman, Britt
Hodgson, Keith O.
Vela, Alberto
Solomon, Edward I.
Quintanar, Liliana
author Arcos López, Trinidad
author_facet Arcos López, Trinidad
Qayyum, Munzarin
Rivillas Acevedo, Lina
Miotto, Marco César
Grande Aztatzi, Rafael
Fernandez, Claudio Oscar
Hedman, Britt
Hodgson, Keith O.
Vela, Alberto
Solomon, Edward I.
Quintanar, Liliana
author_role author
author2 Qayyum, Munzarin
Rivillas Acevedo, Lina
Miotto, Marco César
Grande Aztatzi, Rafael
Fernandez, Claudio Oscar
Hedman, Britt
Hodgson, Keith O.
Vela, Alberto
Solomon, Edward I.
Quintanar, Liliana
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cu(I)
Prion Protein
Biophysics
topic Cu(I)
Prion Protein
Biophysics
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 ability of the cellular prion protein (PrPC) to bind copper in vivo points to a physiological role for PrPC in copper transport. Six copper binding sites have been identified in the nonstructured N-terminal region of human PrPC. Among these sites, the His111 site is unique in that it contains a MKHM motif that would confer interesting CuI and CuII binding properties. We have evaluated CuI coordination to the PrP(106-115) fragment of the human PrP protein, using NMR and X-ray absorption spectroscopies and electronic structure calculations. We find that Met109 and Met112 play an important role in anchoring this metal ion. CuI coordination to His111 is pH-dependent: at pH >8, 2N1O1S species are formed with one Met ligand; in the range of pH 5-8, both methionine (Met) residues bind to CuI, forming a 1N1O2S species, where N is from His111 and O is from a backbone carbonyl or a water molecule; at pH <5, only the two Met residues remain coordinated. Thus, even upon drastic changes in the chemical environment, such as those occurring during endocytosis of PrPC (decreased pH and a reducing potential), the two Met residues in the MKHM motif enable PrPC to maintain the bound CuI ions, consistent with a copper transport function for this protein. We also find that the physiologically relevant CuI-1N1O2S species activates dioxygen via an inner-sphere mechanism, likely involving the formation of a copper(II) superoxide complex. In this process, the Met residues are partially oxidized to sulfoxide; this ability to scavenge superoxide may play a role in the proposed antioxidant properties of PrPC. This study provides further insight into the CuI coordination properties of His111 in human PrPC and the molecular mechanism of oxygen activation by this site.
Fil: Arcos López, Trinidad. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Fil: Qayyum, Munzarin. University of Stanford; Estados Unidos
Fil: Rivillas Acevedo, Lina. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Fil: Miotto, Marco César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Max Planck Laboratory for Structural Biology; Argentina
Fil: Grande Aztatzi, Rafael. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Max Planck Laboratory for Structural Biology; Argentina
Fil: Hedman, Britt. University of Stanford; Estados Unidos
Fil: Hodgson, Keith O.. University of Stanford; Estados Unidos
Fil: Vela, Alberto. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
Fil: Solomon, Edward I.. University of Stanford; Estados Unidos
Fil: Quintanar, Liliana. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; México
description The ability of the cellular prion protein (PrPC) to bind copper in vivo points to a physiological role for PrPC in copper transport. Six copper binding sites have been identified in the nonstructured N-terminal region of human PrPC. Among these sites, the His111 site is unique in that it contains a MKHM motif that would confer interesting CuI and CuII binding properties. We have evaluated CuI coordination to the PrP(106-115) fragment of the human PrP protein, using NMR and X-ray absorption spectroscopies and electronic structure calculations. We find that Met109 and Met112 play an important role in anchoring this metal ion. CuI coordination to His111 is pH-dependent: at pH >8, 2N1O1S species are formed with one Met ligand; in the range of pH 5-8, both methionine (Met) residues bind to CuI, forming a 1N1O2S species, where N is from His111 and O is from a backbone carbonyl or a water molecule; at pH <5, only the two Met residues remain coordinated. Thus, even upon drastic changes in the chemical environment, such as those occurring during endocytosis of PrPC (decreased pH and a reducing potential), the two Met residues in the MKHM motif enable PrPC to maintain the bound CuI ions, consistent with a copper transport function for this protein. We also find that the physiologically relevant CuI-1N1O2S species activates dioxygen via an inner-sphere mechanism, likely involving the formation of a copper(II) superoxide complex. In this process, the Met residues are partially oxidized to sulfoxide; this ability to scavenge superoxide may play a role in the proposed antioxidant properties of PrPC. This study provides further insight into the CuI coordination properties of His111 in human PrPC and the molecular mechanism of oxygen activation by this site.
publishDate 2016
dc.date.none.fl_str_mv 2016-03
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/11336/52826
Arcos López, Trinidad; Qayyum, Munzarin; Rivillas Acevedo, Lina; Miotto, Marco César; Grande Aztatzi, Rafael; et al.; Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115; American Chemical Society; Inorganic Chemistry; 55; 6; 3-2016; 2909-2922
0020-1669
CONICET Digital
CONICET
url http://hdl.handle.net/11336/52826
identifier_str_mv Arcos López, Trinidad; Qayyum, Munzarin; Rivillas Acevedo, Lina; Miotto, Marco César; Grande Aztatzi, Rafael; et al.; Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115; American Chemical Society; Inorganic Chemistry; 55; 6; 3-2016; 2909-2922
0020-1669
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.inorgchem.5b02794
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.inorgchem.5b02794
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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score 12.982451

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