The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis
- Autores
- Llovera, Ramiro Esteban; de Tullio, Matias Blas; Alonso, Leonardo Gabriel; Leissring, Malcolm A.; Kaufman, Sergio Benjamín; Roher, Alex E.; de Prat Gay, Gonzalo; Morelli, Laura; Castaño, Eduardo Miguel
- Año de publicación
- 2008
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid β (Aβ) in the mammalian brain. Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively folded recombinant IDE was capable of forming a stable complex with Aβ that resisted dissociation after treatment with strong denaturants. This interaction was also observed with rat brain IDE and detected in an SDS-soluble fraction from AD cortical tissue. Aβ sequence 17-27, known to be crucial in amyloid assembly, was sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated Aβ was competent to associate irreversibly with IDE following a very slow kinetics (t1/2 ∼ 45 min). Partial denaturation of IDE as well as preincubation with a 10-fold molar excess of insulin prevented complex formation, suggesting that the irreversible interaction of Aβ takes place with at least part of the substrate binding site of the protease. Limited proteolysis showed that Aβ remained bound to a ∼25-kDa N-terminal fragment of IDE in an SDS-resistant manner. Mass spectrometry after in gel digestion of the IDE·Aβ complex showed that peptides derived from the region that includes the catalytic site of IDE were recovered with Aβ. Taken together, these results are suggestive of an unprecedented mechanism of conformation-dependent substrate binding that may perturb Aβ clearance, insulin turnover, and promote AD pathogenesis.
Fil: Llovera, Ramiro Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
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. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Alonso, Leonardo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Leissring, Malcolm A.. The Scripps Research Institute; Estados Unidos
Fil: Kaufman, Sergio Benjamín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina
Fil: Roher, Alex E.. Banner Sun Health Research Institute; Estados Unidos
Fil: de Prat Gay, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; 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. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina - Materia
-
Alzheimer
amyloid
insulin-degrading enzyme - 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:11336/38514
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oai:ri.conicet.gov.ar:11336/38514 |
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The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesisLlovera, Ramiro Estebande Tullio, Matias BlasAlonso, Leonardo GabrielLeissring, Malcolm A.Kaufman, Sergio BenjamínRoher, Alex E.de Prat Gay, GonzaloMorelli, LauraCastaño, Eduardo MiguelAlzheimeramyloidinsulin-degrading enzymehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid β (Aβ) in the mammalian brain. Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively folded recombinant IDE was capable of forming a stable complex with Aβ that resisted dissociation after treatment with strong denaturants. This interaction was also observed with rat brain IDE and detected in an SDS-soluble fraction from AD cortical tissue. Aβ sequence 17-27, known to be crucial in amyloid assembly, was sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated Aβ was competent to associate irreversibly with IDE following a very slow kinetics (t1/2 ∼ 45 min). Partial denaturation of IDE as well as preincubation with a 10-fold molar excess of insulin prevented complex formation, suggesting that the irreversible interaction of Aβ takes place with at least part of the substrate binding site of the protease. Limited proteolysis showed that Aβ remained bound to a ∼25-kDa N-terminal fragment of IDE in an SDS-resistant manner. Mass spectrometry after in gel digestion of the IDE·Aβ complex showed that peptides derived from the region that includes the catalytic site of IDE were recovered with Aβ. Taken together, these results are suggestive of an unprecedented mechanism of conformation-dependent substrate binding that may perturb Aβ clearance, insulin turnover, and promote AD pathogenesis.Fil: Llovera, Ramiro Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: de Tullio, Matias Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Alonso, Leonardo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Leissring, Malcolm A.. The Scripps Research Institute; Estados UnidosFil: Kaufman, Sergio Benjamín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; ArgentinaFil: Roher, Alex E.. Banner Sun Health Research Institute; Estados UnidosFil: de Prat Gay, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaAmerican Society for Biochemistry and Molecular Biology2008-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/38514Llovera, Ramiro Esteban; de Tullio, Matias Blas; Alonso, Leonardo Gabriel; Leissring, Malcolm A.; Kaufman, Sergio Benjamín; et al.; The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 283; 25; 6-2008; 17039-170480021-92581083-351XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/283/25/17039.longinfo:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M706316200info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:11:52Zoai:ri.conicet.gov.ar:11336/38514instacron: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 10:11:52.468CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis |
title |
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis |
spellingShingle |
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis Llovera, Ramiro Esteban Alzheimer amyloid insulin-degrading enzyme |
title_short |
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis |
title_full |
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis |
title_fullStr |
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis |
title_full_unstemmed |
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis |
title_sort |
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis |
dc.creator.none.fl_str_mv |
Llovera, Ramiro Esteban de Tullio, Matias Blas Alonso, Leonardo Gabriel Leissring, Malcolm A. Kaufman, Sergio Benjamín Roher, Alex E. de Prat Gay, Gonzalo Morelli, Laura Castaño, Eduardo Miguel |
author |
Llovera, Ramiro Esteban |
author_facet |
Llovera, Ramiro Esteban de Tullio, Matias Blas Alonso, Leonardo Gabriel Leissring, Malcolm A. Kaufman, Sergio Benjamín Roher, Alex E. de Prat Gay, Gonzalo Morelli, Laura Castaño, Eduardo Miguel |
author_role |
author |
author2 |
de Tullio, Matias Blas Alonso, Leonardo Gabriel Leissring, Malcolm A. Kaufman, Sergio Benjamín Roher, Alex E. de Prat Gay, Gonzalo Morelli, Laura Castaño, Eduardo Miguel |
author2_role |
author author author author author author author author |
dc.subject.none.fl_str_mv |
Alzheimer amyloid insulin-degrading enzyme |
topic |
Alzheimer amyloid insulin-degrading enzyme |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid β (Aβ) in the mammalian brain. Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively folded recombinant IDE was capable of forming a stable complex with Aβ that resisted dissociation after treatment with strong denaturants. This interaction was also observed with rat brain IDE and detected in an SDS-soluble fraction from AD cortical tissue. Aβ sequence 17-27, known to be crucial in amyloid assembly, was sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated Aβ was competent to associate irreversibly with IDE following a very slow kinetics (t1/2 ∼ 45 min). Partial denaturation of IDE as well as preincubation with a 10-fold molar excess of insulin prevented complex formation, suggesting that the irreversible interaction of Aβ takes place with at least part of the substrate binding site of the protease. Limited proteolysis showed that Aβ remained bound to a ∼25-kDa N-terminal fragment of IDE in an SDS-resistant manner. Mass spectrometry after in gel digestion of the IDE·Aβ complex showed that peptides derived from the region that includes the catalytic site of IDE were recovered with Aβ. Taken together, these results are suggestive of an unprecedented mechanism of conformation-dependent substrate binding that may perturb Aβ clearance, insulin turnover, and promote AD pathogenesis. Fil: Llovera, Ramiro Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina 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. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Alonso, Leonardo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Leissring, Malcolm A.. The Scripps Research Institute; Estados Unidos Fil: Kaufman, Sergio Benjamín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina Fil: Roher, Alex E.. Banner Sun Health Research Institute; Estados Unidos Fil: de Prat Gay, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; 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. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina |
description |
Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid β (Aβ) in the mammalian brain. Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively folded recombinant IDE was capable of forming a stable complex with Aβ that resisted dissociation after treatment with strong denaturants. This interaction was also observed with rat brain IDE and detected in an SDS-soluble fraction from AD cortical tissue. Aβ sequence 17-27, known to be crucial in amyloid assembly, was sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated Aβ was competent to associate irreversibly with IDE following a very slow kinetics (t1/2 ∼ 45 min). Partial denaturation of IDE as well as preincubation with a 10-fold molar excess of insulin prevented complex formation, suggesting that the irreversible interaction of Aβ takes place with at least part of the substrate binding site of the protease. Limited proteolysis showed that Aβ remained bound to a ∼25-kDa N-terminal fragment of IDE in an SDS-resistant manner. Mass spectrometry after in gel digestion of the IDE·Aβ complex showed that peptides derived from the region that includes the catalytic site of IDE were recovered with Aβ. Taken together, these results are suggestive of an unprecedented mechanism of conformation-dependent substrate binding that may perturb Aβ clearance, insulin turnover, and promote AD pathogenesis. |
publishDate |
2008 |
dc.date.none.fl_str_mv |
2008-06 |
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/11336/38514 Llovera, Ramiro Esteban; de Tullio, Matias Blas; Alonso, Leonardo Gabriel; Leissring, Malcolm A.; Kaufman, Sergio Benjamín; et al.; The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 283; 25; 6-2008; 17039-17048 0021-9258 1083-351X CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/38514 |
identifier_str_mv |
Llovera, Ramiro Esteban; de Tullio, Matias Blas; Alonso, Leonardo Gabriel; Leissring, Malcolm A.; Kaufman, Sergio Benjamín; et al.; The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid β peptide: Implications for Alzheimer disease pathogenesis; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 283; 25; 6-2008; 17039-17048 0021-9258 1083-351X CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/283/25/17039.long info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M706316200 |
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 application/pdf application/pdf application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Society for Biochemistry and Molecular Biology |
publisher.none.fl_str_mv |
American Society for Biochemistry and Molecular Biology |
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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1844614021214371840 |
score |
13.070432 |