Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates

Insulin-degrading enzyme (IDE) is a neutral Zn(2+) peptidase that degrades short peptides based on substrate conformation, size and charge. Some of these substrates, including amyloid â (Aâ) are capable of self-assembling into cytotoxic oligomers. Based on IDE recognition mechanism and our previous...

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Detalhes bibliográficos
Autores: de Tullio, Matias Blas, Castelletto, Valeria, Hamley, Ian W., Martino Adami, Pamela Victoria, Morelli, Laura, Castaño, Eduardo Miguel
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2013
País:Argentina
Recursos:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/1685
Acesso em linha:http://hdl.handle.net/11336/1685
Access Level:acceso abierto
Palavra-chave:INSULIN DEGRADING ENZYME
ABETA
OLIGOMERS
CHAPERONE
ENZYME STRUCTURE
HYDROLYSIS
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
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oai_identifier_str oai:ri.conicet.gov.ar:11336/1685
network_acronym_str AR
network_name_str Argentina
repository_id_str
dc.title.none.fl_str_mv Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates
title Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates
spellingShingle Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates
de Tullio, Matias Blas
INSULIN DEGRADING ENZYME
ABETA
OLIGOMERS
CHAPERONE
ENZYME STRUCTURE
HYDROLYSIS
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
title_short Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates
title_full Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates
title_fullStr Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates
title_full_unstemmed Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates
title_sort Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates
dc.creator.none.fl_str_mv de Tullio, Matias Blas
Castelletto, Valeria
Hamley, Ian W.
Martino Adami, Pamela Victoria
Morelli, Laura
Castaño, Eduardo Miguel
author de Tullio, Matias Blas
author_facet de Tullio, Matias Blas
Castelletto, Valeria
Hamley, Ian W.
Martino Adami, Pamela Victoria
Morelli, Laura
Castaño, Eduardo Miguel
author_role author
author2 Castelletto, Valeria
Hamley, Ian W.
Martino Adami, Pamela Victoria
Morelli, Laura
Castaño, Eduardo Miguel
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv INSULIN DEGRADING ENZYME
ABETA
OLIGOMERS
CHAPERONE
ENZYME STRUCTURE
HYDROLYSIS
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
topic INSULIN DEGRADING ENZYME
ABETA
OLIGOMERS
CHAPERONE
ENZYME STRUCTURE
HYDROLYSIS
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
description Insulin-degrading enzyme (IDE) is a neutral Zn(2+) peptidase that degrades short peptides based on substrate conformation, size and charge. Some of these substrates, including amyloid â (Aâ) are capable of self-assembling into cytotoxic oligomers. Based on IDE recognition mechanism and our previous report of the formation of a stable complex between IDE and intact Aâ in vitro and in vivo, we analyzed the possibility of a chaperone-like function of IDE. A proteolytically inactive recombinant IDE with Glu111 replaced by Gln (IDEQ) was used. IDEQ blocked the amyloidogenic pathway of Aâ yielding non-fibrillar structures as assessed by electron microscopy. Measurements of the kinetics of Abeta aggregation by light scattering showed that 1) IDEQ effect was promoted by ATP independent of its hydrolysis, 2) end products of Abeta-IDEQ co-incubation were incapable of "seeding" the assembly of monomeric Abeta and 3) IDEQ was ineffective in reversing Aâ aggregation. Moreover, Abeta aggregates formed in the presence of IDEQ were non-neurotoxic. IDEQ had no conformational effects upon insulin (a non-amyloidogenic protein under physiological conditions) and did not disturb insulin receptor activation in cultured cells. Our results suggest that IDE has a chaperone-like activity upon amyloid-forming peptides. It remains to be explored whether other highly conserved metallopeptidases have a dual protease-chaperone function to prevent the formation of toxic peptide oligomers from bacteria to mammals.
publishDate 2013
dc.date.none.fl_str_mv 2013-04-11
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/11336/1685
de Tullio, Matias Blas; Castelletto, Valeria; Hamley, Ian W.; Martino Adami, Pamela Victoria; Morelli, Laura; et al.; Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates; Public Library of Science; Plos One; 8; 4; 11-4-2013; 1-13
1932-6203
url http://hdl.handle.net/11336/1685
identifier_str_mv de Tullio, Matias Blas; Castelletto, Valeria; Hamley, Ian W.; Martino Adami, Pamela Victoria; Morelli, Laura; et al.; Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates; Public Library of Science; Plos One; 8; 4; 11-4-2013; 1-13
1932-6203
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/DOI:10.1371/journal.pone.0059113
info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059113
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 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
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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_ 1799195202256109568
spelling Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregatesde Tullio, Matias BlasCastelletto, ValeriaHamley, Ian W.Martino Adami, Pamela VictoriaMorelli, LauraCastaño, Eduardo MiguelINSULIN DEGRADING ENZYMEABETAOLIGOMERSCHAPERONEENZYME STRUCTUREHYDROLYSIShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Insulin-degrading enzyme (IDE) is a neutral Zn(2+) peptidase that degrades short peptides based on substrate conformation, size and charge. Some of these substrates, including amyloid â (Aâ) are capable of self-assembling into cytotoxic oligomers. Based on IDE recognition mechanism and our previous report of the formation of a stable complex between IDE and intact Aâ in vitro and in vivo, we analyzed the possibility of a chaperone-like function of IDE. A proteolytically inactive recombinant IDE with Glu111 replaced by Gln (IDEQ) was used. IDEQ blocked the amyloidogenic pathway of Aâ yielding non-fibrillar structures as assessed by electron microscopy. Measurements of the kinetics of Abeta aggregation by light scattering showed that 1) IDEQ effect was promoted by ATP independent of its hydrolysis, 2) end products of Abeta-IDEQ co-incubation were incapable of "seeding" the assembly of monomeric Abeta and 3) IDEQ was ineffective in reversing Aâ aggregation. Moreover, Abeta aggregates formed in the presence of IDEQ were non-neurotoxic. IDEQ had no conformational effects upon insulin (a non-amyloidogenic protein under physiological conditions) and did not disturb insulin receptor activation in cultured cells. Our results suggest that IDE has a chaperone-like activity upon amyloid-forming peptides. It remains to be explored whether other highly conserved metallopeptidases have a dual protease-chaperone function to prevent the formation of toxic peptide oligomers from bacteria to mammals.Fil: de Tullio, Matias Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina;Fil: Castelletto, Valeria.Fil: Hamley, Ian W..Fil: Martino Adami, Pamela Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina;Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina;Fil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina;Public Library of Science2013-04-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/1685de Tullio, Matias Blas; Castelletto, Valeria; Hamley, Ian W.; Martino Adami, Pamela Victoria; Morelli, Laura; et al.; Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic ABeta peptide aggregates; Public Library of Science; Plos One; 8; 4; 11-4-2013; 1-131932-6203enginfo:eu-repo/semantics/altIdentifier/doi/DOI:10.1371/journal.pone.0059113info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059113info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2024-05-08T13:46:01Zoai:ri.conicet.gov.ar:11336/1685instacron: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:34982024-05-08 13:46:01.589CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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