Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide

Autores
Sánchez López, Carolina; Cortés Mejía, Rodrigo; Miotto, Marco César; Binolfi, Andrés; Fernandez, Claudio Oscar; Del Campo, Jorge M.; Quintanar, Liliana
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in pancreatic β-cells of patients with type 2 diabetes (T2D). Copper ions have an inhibitory effect on the amyloid aggregation of hIAPP, and they may play a role in the etiology of T2D. However, deeper knowledge of the structural details of the copper-hIAPP interaction is required to understand the molecular mechanisms involved. Here, we performed a spectroscopic study of Cu(II) binding to hIAPP and several variants, using electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), electronic absorption, and circular dichroism (CD) in the UV-vis region in combination with Born-Oppenheimer molecular dynamics (BOMD) and density functional theory geometry optimizations. We find that Cu(II) binds to the imidazole N1 of His18, the deprotonated amides of Ser19 and Ser20, and an oxygen-based ligand provided by Ser20, either via its hydroxyl group or its backbone carbonyl, while Asn22 might also play a role as an axial ligand. Ser20 plays a crucial role in stabilizing Cu(II) coordination toward the C-terminal, providing a potential link between the S20G mutation associated with early onset of T2D, its impact in Cu binding properties, and hIAPP amyloid aggregation. Our study defines the nature of the coordination environment in the Cu(II)-hIAPP complex, revealing that the amino acid residues involved in metal ion binding are also key residues for the formation of β-sheet structures and amyloid fibrils. Cu(II) binding to hIAPP may lead to the coexistence of more than one coordination mode, which in turn could favor different sets of Cu-induced conformational ensembles. Cu-induced hIAPP conformers would display a higher energetic barrier to form amyloid fibrils, hence explaining the inhibitory effect of Cu ions in hIAPP aggregation. Overall, this study provides further structural insights into the bioinorganic chemistry of T2D.
Fil: Sánchez López, Carolina. Centro de Investigación y de Estudios Avanzados. Departamento de Química; México
Fil: Cortés Mejía, Rodrigo. Universidad Nacional Autónoma de México; 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: Binolfi, Andrés. 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: 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: Del Campo, Jorge M.. Universidad Nacional Autónoma de México; México
Fil: Quintanar, Liliana. Centro de Investigación y de Estudios Avanzados. Departamento de Química; México
Materia
COPPER
DIABETES
BIOINORGANIC
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:11336/52702
Acceder
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spelling Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes PeptideSánchez López, CarolinaCortés Mejía, RodrigoMiotto, Marco CésarBinolfi, AndrésFernandez, Claudio OscarDel Campo, Jorge M.Quintanar, LilianaCOPPERDIABETESBIOINORGANICBIOPHYSICShttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in pancreatic β-cells of patients with type 2 diabetes (T2D). Copper ions have an inhibitory effect on the amyloid aggregation of hIAPP, and they may play a role in the etiology of T2D. However, deeper knowledge of the structural details of the copper-hIAPP interaction is required to understand the molecular mechanisms involved. Here, we performed a spectroscopic study of Cu(II) binding to hIAPP and several variants, using electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), electronic absorption, and circular dichroism (CD) in the UV-vis region in combination with Born-Oppenheimer molecular dynamics (BOMD) and density functional theory geometry optimizations. We find that Cu(II) binds to the imidazole N1 of His18, the deprotonated amides of Ser19 and Ser20, and an oxygen-based ligand provided by Ser20, either via its hydroxyl group or its backbone carbonyl, while Asn22 might also play a role as an axial ligand. Ser20 plays a crucial role in stabilizing Cu(II) coordination toward the C-terminal, providing a potential link between the S20G mutation associated with early onset of T2D, its impact in Cu binding properties, and hIAPP amyloid aggregation. Our study defines the nature of the coordination environment in the Cu(II)-hIAPP complex, revealing that the amino acid residues involved in metal ion binding are also key residues for the formation of β-sheet structures and amyloid fibrils. Cu(II) binding to hIAPP may lead to the coexistence of more than one coordination mode, which in turn could favor different sets of Cu-induced conformational ensembles. Cu-induced hIAPP conformers would display a higher energetic barrier to form amyloid fibrils, hence explaining the inhibitory effect of Cu ions in hIAPP aggregation. Overall, this study provides further structural insights into the bioinorganic chemistry of T2D.Fil: Sánchez López, Carolina. Centro de Investigación y de Estudios Avanzados. Departamento de Química; MéxicoFil: Cortés Mejía, Rodrigo. Universidad Nacional Autónoma de México; 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: Binolfi, Andrés. 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: 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: Del Campo, Jorge M.. Universidad Nacional Autónoma de México; MéxicoFil: Quintanar, Liliana. Centro de Investigación y de Estudios Avanzados. Departamento de Química; MéxicoAmerican Chemical Society2016-10info: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/11336/52702Sánchez López, Carolina; Cortés Mejía, Rodrigo; Miotto, Marco César; Binolfi, Andrés; Fernandez, Claudio Oscar; et al.; Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide; American Chemical Society; Inorganic Chemistry; 55; 20; 10-2016; 10727-107400020-1669CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/acs.inorgchem.6b01963info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.inorgchem.6b01963info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:38:43Zoai:ri.conicet.gov.ar:11336/52702instacron: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 10:38:43.459CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
title Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
spellingShingle Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
Sánchez López, Carolina
COPPER
DIABETES
BIOINORGANIC
BIOPHYSICS
title_short Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
title_full Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
title_fullStr Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
title_full_unstemmed Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
title_sort Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide
dc.creator.none.fl_str_mv Sánchez López, Carolina
Cortés Mejía, Rodrigo
Miotto, Marco César
Binolfi, Andrés
Fernandez, Claudio Oscar
Del Campo, Jorge M.
Quintanar, Liliana
author Sánchez López, Carolina
author_facet Sánchez López, Carolina
Cortés Mejía, Rodrigo
Miotto, Marco César
Binolfi, Andrés
Fernandez, Claudio Oscar
Del Campo, Jorge M.
Quintanar, Liliana
author_role author
author2 Cortés Mejía, Rodrigo
Miotto, Marco César
Binolfi, Andrés
Fernandez, Claudio Oscar
Del Campo, Jorge M.
Quintanar, Liliana
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv COPPER
DIABETES
BIOINORGANIC
BIOPHYSICS
topic COPPER
DIABETES
BIOINORGANIC
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 Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in pancreatic β-cells of patients with type 2 diabetes (T2D). Copper ions have an inhibitory effect on the amyloid aggregation of hIAPP, and they may play a role in the etiology of T2D. However, deeper knowledge of the structural details of the copper-hIAPP interaction is required to understand the molecular mechanisms involved. Here, we performed a spectroscopic study of Cu(II) binding to hIAPP and several variants, using electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), electronic absorption, and circular dichroism (CD) in the UV-vis region in combination with Born-Oppenheimer molecular dynamics (BOMD) and density functional theory geometry optimizations. We find that Cu(II) binds to the imidazole N1 of His18, the deprotonated amides of Ser19 and Ser20, and an oxygen-based ligand provided by Ser20, either via its hydroxyl group or its backbone carbonyl, while Asn22 might also play a role as an axial ligand. Ser20 plays a crucial role in stabilizing Cu(II) coordination toward the C-terminal, providing a potential link between the S20G mutation associated with early onset of T2D, its impact in Cu binding properties, and hIAPP amyloid aggregation. Our study defines the nature of the coordination environment in the Cu(II)-hIAPP complex, revealing that the amino acid residues involved in metal ion binding are also key residues for the formation of β-sheet structures and amyloid fibrils. Cu(II) binding to hIAPP may lead to the coexistence of more than one coordination mode, which in turn could favor different sets of Cu-induced conformational ensembles. Cu-induced hIAPP conformers would display a higher energetic barrier to form amyloid fibrils, hence explaining the inhibitory effect of Cu ions in hIAPP aggregation. Overall, this study provides further structural insights into the bioinorganic chemistry of T2D.
Fil: Sánchez López, Carolina. Centro de Investigación y de Estudios Avanzados. Departamento de Química; México
Fil: Cortés Mejía, Rodrigo. Universidad Nacional Autónoma de México; 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: Binolfi, Andrés. 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: 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: Del Campo, Jorge M.. Universidad Nacional Autónoma de México; México
Fil: Quintanar, Liliana. Centro de Investigación y de Estudios Avanzados. Departamento de Química; México
description Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in pancreatic β-cells of patients with type 2 diabetes (T2D). Copper ions have an inhibitory effect on the amyloid aggregation of hIAPP, and they may play a role in the etiology of T2D. However, deeper knowledge of the structural details of the copper-hIAPP interaction is required to understand the molecular mechanisms involved. Here, we performed a spectroscopic study of Cu(II) binding to hIAPP and several variants, using electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), electronic absorption, and circular dichroism (CD) in the UV-vis region in combination with Born-Oppenheimer molecular dynamics (BOMD) and density functional theory geometry optimizations. We find that Cu(II) binds to the imidazole N1 of His18, the deprotonated amides of Ser19 and Ser20, and an oxygen-based ligand provided by Ser20, either via its hydroxyl group or its backbone carbonyl, while Asn22 might also play a role as an axial ligand. Ser20 plays a crucial role in stabilizing Cu(II) coordination toward the C-terminal, providing a potential link between the S20G mutation associated with early onset of T2D, its impact in Cu binding properties, and hIAPP amyloid aggregation. Our study defines the nature of the coordination environment in the Cu(II)-hIAPP complex, revealing that the amino acid residues involved in metal ion binding are also key residues for the formation of β-sheet structures and amyloid fibrils. Cu(II) binding to hIAPP may lead to the coexistence of more than one coordination mode, which in turn could favor different sets of Cu-induced conformational ensembles. Cu-induced hIAPP conformers would display a higher energetic barrier to form amyloid fibrils, hence explaining the inhibitory effect of Cu ions in hIAPP aggregation. Overall, this study provides further structural insights into the bioinorganic chemistry of T2D.
publishDate 2016
dc.date.none.fl_str_mv 2016-10
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/11336/52702
Sánchez López, Carolina; Cortés Mejía, Rodrigo; Miotto, Marco César; Binolfi, Andrés; Fernandez, Claudio Oscar; et al.; Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide; American Chemical Society; Inorganic Chemistry; 55; 20; 10-2016; 10727-10740
0020-1669
CONICET Digital
CONICET
url http://hdl.handle.net/11336/52702
identifier_str_mv Sánchez López, Carolina; Cortés Mejía, Rodrigo; Miotto, Marco César; Binolfi, Andrés; Fernandez, Claudio Oscar; et al.; Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide; American Chemical Society; Inorganic Chemistry; 55; 20; 10-2016; 10727-10740
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.6b01963
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.inorgchem.6b01963
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 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 13.070432

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