The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid β Peptide
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Le résumé fourni par la source
Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid beta (Abeta) 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 Abeta 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. Abeta sequence 17-27, known to be crucial in amyloid assembly, was sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated Abeta was competent to associate irreversibly with IDE following a very slow kinetics (t(1/2) approximately 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 Abeta takes place with at least part of the substrate binding site of the protease. Limited proteolysis showed that Abeta remained bound to a approximately 25-kDa N-terminal fragment of IDE in an SDS-resistant manner. Mass spectrometry after in gel digestion of the IDE .Abeta complex showed that peptides derived from the region that includes the catalytic site of IDE were recovered with Abeta. Taken together, these results are suggestive of an unprecedented mechanism of conformation-dependent substrate binding that may perturb Abeta clearance, insulin turnover, and promote AD pathogenesis.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid β Peptide
- Date Crossref
- 01/06/2008
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Consejo Nacional de Investigaciones Científicas y Técnicas pays non établi dans la noticeOrganisme public
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Fundación Instituto Leloir pays non établi dans la noticeStructure de recherche
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Scripps (United States) pays non établi dans la noticeEntreprise
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Universidad de Buenos Aires pays non établi dans la noticeUniversité ou école supérieure
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Instituto de Química y Fisicoquímica Biológicas pays non établi dans la noticeStructure de recherche
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Banner Health pays non établi dans la noticeÉtablissement de santé
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Department of Biomedical Sciences pays non établi dans la noticeInstitution
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Sun Health Research Institute pays non établi dans la noticeStructure de recherche
Consejo Nacional de Investigaciones Científicas y Técnicas, Fundación Instituto Leloir et Scripps (United States), avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.