Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease

Autores
Fernandez Gamba, Agata Claudia; Leal, Maria Celeste; Morelli, Laura; Castaño, Eduardo Miguel
Año de publicación
2009
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Insulin-degrading enzyme (IDE) or insulysin is a highly conserved Zn 2+-dependent endopeptidase with an "inverted" HxxEH motif. In vivo, IDE contributes to regulate the steady state levels of peripheral insulin and cerebral amyloid β peptide (Aβ) of Alzheimer's disease. In vitro, substrates of IDE include a broad spectrum of peptides with relevant physiological functions such as atrial natriuretic factor, insulin-like growth factor-II, transforming growth factor-α, β-endorphin, amylin or glucagon. The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity. IDE-N and IDE-C halves contribute to substrate binding and may rotate away from each other leading to open and closed conformers that permit or preclude the entry of substrates. Noteworthy, stabilization of substrate β strands in their IDE-bound form may explain the preference of IDE for peptides with a high tendency to self-assembly as amyloid fibrils. These structural requirements may underlie the capability of some amyloid peptides of forming extremely stable complexes with IDE and raise the possibility of a dead-end chaperone-like function of IDE independent of catalysis. Furthermore, the recent recognition of IDE as a varicella zoster virus receptor and its putative involvement in muscle cell differentiation, steroid receptor signaling or proteasome modulation suggest that IDE is a multi-functional protein with broad and relevant roles in several basic cellular processes. Accordingly, IDE functions, regulation or trafficking may partake in the molecular pathogenesis of major human diseases and become potential targets for therapeutic intervention.
Fil: Fernandez Gamba, Agata Claudia. 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: Leal, Maria Celeste. 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 Β
DIABETES MELLITUS TYPE 2
INSULIN DEGRADING ENZYME
INSULYSIN
METALLOPEPTIDASES
PEPTIDES
VARICELLA ZOSTER VIRUS
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:11336/137874
Acceder
id CONICETDig_61a4befdce1a53f9274ae881fe133d52
oai_identifier_str oai:ri.conicet.gov.ar:11336/137874
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and diseaseFernandez Gamba, Agata ClaudiaLeal, Maria CelesteMorelli, LauraCastaño, Eduardo MiguelALZHEIMERAMYLOID ΒDIABETES MELLITUS TYPE 2INSULIN DEGRADING ENZYMEINSULYSINMETALLOPEPTIDASESPEPTIDESVARICELLA ZOSTER VIRUShttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Insulin-degrading enzyme (IDE) or insulysin is a highly conserved Zn 2+-dependent endopeptidase with an "inverted" HxxEH motif. In vivo, IDE contributes to regulate the steady state levels of peripheral insulin and cerebral amyloid β peptide (Aβ) of Alzheimer's disease. In vitro, substrates of IDE include a broad spectrum of peptides with relevant physiological functions such as atrial natriuretic factor, insulin-like growth factor-II, transforming growth factor-α, β-endorphin, amylin or glucagon. The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity. IDE-N and IDE-C halves contribute to substrate binding and may rotate away from each other leading to open and closed conformers that permit or preclude the entry of substrates. Noteworthy, stabilization of substrate β strands in their IDE-bound form may explain the preference of IDE for peptides with a high tendency to self-assembly as amyloid fibrils. These structural requirements may underlie the capability of some amyloid peptides of forming extremely stable complexes with IDE and raise the possibility of a dead-end chaperone-like function of IDE independent of catalysis. Furthermore, the recent recognition of IDE as a varicella zoster virus receptor and its putative involvement in muscle cell differentiation, steroid receptor signaling or proteasome modulation suggest that IDE is a multi-functional protein with broad and relevant roles in several basic cellular processes. Accordingly, IDE functions, regulation or trafficking may partake in the molecular pathogenesis of major human diseases and become potential targets for therapeutic intervention.Fil: Fernandez Gamba, Agata Claudia. 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: Leal, Maria Celeste. 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; ArgentinaBentham Science Publishers2009-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/137874Fernandez Gamba, Agata Claudia; Leal, Maria Celeste; Morelli, Laura; Castaño, Eduardo Miguel; Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease; Bentham Science Publishers; Current Pharmaceutical Design; 15; 31; 11-2009; 3644-36551381-61281873-4286CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.eurekaselect.com/70146/articleinfo:eu-repo/semantics/altIdentifier/doi/10.2174/138161209789271799info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:05:02Zoai:ri.conicet.gov.ar:11336/137874instacron: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:34982025-10-15 15:05:02.687CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease
title Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease
spellingShingle Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease
Fernandez Gamba, Agata Claudia
ALZHEIMER
AMYLOID Β
DIABETES MELLITUS TYPE 2
INSULIN DEGRADING ENZYME
INSULYSIN
METALLOPEPTIDASES
PEPTIDES
VARICELLA ZOSTER VIRUS
title_short Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease
title_full Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease
title_fullStr Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease
title_full_unstemmed Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease
title_sort Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease
dc.creator.none.fl_str_mv Fernandez Gamba, Agata Claudia
Leal, Maria Celeste
Morelli, Laura
Castaño, Eduardo Miguel
author Fernandez Gamba, Agata Claudia
author_facet Fernandez Gamba, Agata Claudia
Leal, Maria Celeste
Morelli, Laura
Castaño, Eduardo Miguel
author_role author
author2 Leal, Maria Celeste
Morelli, Laura
Castaño, Eduardo Miguel
author2_role author
author
author
dc.subject.none.fl_str_mv ALZHEIMER
AMYLOID Β
DIABETES MELLITUS TYPE 2
INSULIN DEGRADING ENZYME
INSULYSIN
METALLOPEPTIDASES
PEPTIDES
VARICELLA ZOSTER VIRUS
topic ALZHEIMER
AMYLOID Β
DIABETES MELLITUS TYPE 2
INSULIN DEGRADING ENZYME
INSULYSIN
METALLOPEPTIDASES
PEPTIDES
VARICELLA ZOSTER VIRUS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Insulin-degrading enzyme (IDE) or insulysin is a highly conserved Zn 2+-dependent endopeptidase with an "inverted" HxxEH motif. In vivo, IDE contributes to regulate the steady state levels of peripheral insulin and cerebral amyloid β peptide (Aβ) of Alzheimer's disease. In vitro, substrates of IDE include a broad spectrum of peptides with relevant physiological functions such as atrial natriuretic factor, insulin-like growth factor-II, transforming growth factor-α, β-endorphin, amylin or glucagon. The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity. IDE-N and IDE-C halves contribute to substrate binding and may rotate away from each other leading to open and closed conformers that permit or preclude the entry of substrates. Noteworthy, stabilization of substrate β strands in their IDE-bound form may explain the preference of IDE for peptides with a high tendency to self-assembly as amyloid fibrils. These structural requirements may underlie the capability of some amyloid peptides of forming extremely stable complexes with IDE and raise the possibility of a dead-end chaperone-like function of IDE independent of catalysis. Furthermore, the recent recognition of IDE as a varicella zoster virus receptor and its putative involvement in muscle cell differentiation, steroid receptor signaling or proteasome modulation suggest that IDE is a multi-functional protein with broad and relevant roles in several basic cellular processes. Accordingly, IDE functions, regulation or trafficking may partake in the molecular pathogenesis of major human diseases and become potential targets for therapeutic intervention.
Fil: Fernandez Gamba, Agata Claudia. 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: Leal, Maria Celeste. 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) or insulysin is a highly conserved Zn 2+-dependent endopeptidase with an "inverted" HxxEH motif. In vivo, IDE contributes to regulate the steady state levels of peripheral insulin and cerebral amyloid β peptide (Aβ) of Alzheimer's disease. In vitro, substrates of IDE include a broad spectrum of peptides with relevant physiological functions such as atrial natriuretic factor, insulin-like growth factor-II, transforming growth factor-α, β-endorphin, amylin or glucagon. The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity. IDE-N and IDE-C halves contribute to substrate binding and may rotate away from each other leading to open and closed conformers that permit or preclude the entry of substrates. Noteworthy, stabilization of substrate β strands in their IDE-bound form may explain the preference of IDE for peptides with a high tendency to self-assembly as amyloid fibrils. These structural requirements may underlie the capability of some amyloid peptides of forming extremely stable complexes with IDE and raise the possibility of a dead-end chaperone-like function of IDE independent of catalysis. Furthermore, the recent recognition of IDE as a varicella zoster virus receptor and its putative involvement in muscle cell differentiation, steroid receptor signaling or proteasome modulation suggest that IDE is a multi-functional protein with broad and relevant roles in several basic cellular processes. Accordingly, IDE functions, regulation or trafficking may partake in the molecular pathogenesis of major human diseases and become potential targets for therapeutic intervention.
publishDate 2009
dc.date.none.fl_str_mv 2009-11
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/11336/137874
Fernandez Gamba, Agata Claudia; Leal, Maria Celeste; Morelli, Laura; Castaño, Eduardo Miguel; Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease; Bentham Science Publishers; Current Pharmaceutical Design; 15; 31; 11-2009; 3644-3655
1381-6128
1873-4286
CONICET Digital
CONICET
url http://hdl.handle.net/11336/137874
identifier_str_mv Fernandez Gamba, Agata Claudia; Leal, Maria Celeste; Morelli, Laura; Castaño, Eduardo Miguel; Insulin-degrading enzyme: Structure-function relationship and its possible roles in health and disease; Bentham Science Publishers; Current Pharmaceutical Design; 15; 31; 11-2009; 3644-3655
1381-6128
1873-4286
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://www.eurekaselect.com/70146/article
info:eu-repo/semantics/altIdentifier/doi/10.2174/138161209789271799
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
dc.publisher.none.fl_str_mv Bentham Science Publishers
publisher.none.fl_str_mv Bentham Science Publishers
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 13.22299

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