The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme: a biological perspective.
Insulin-degrading enzyme (IDE) is a conserved Zn(2+)metalloendopeptidase involved in insulin degradation and in the maintenance of brain steady-state levels of amyloid beta peptide (Abeta) of Alzheimer's disease (AD). Our recent demonstration that IDE and Abeta are capable of forming a stoichiometric and extremely stable complex raises several intriguing possibilities regarding the role of this unique protein-peptide interaction in physiological and pathological conditions. These include a protective cellular function of IDE as a "dead-end chaperone" alternative to its proteolytic activity and the potential impact of the irreversible binding of Abeta to IDE upon its role as a varicella zoster virus receptor. In a pathological context, the implications for insulin signaling and its relationship to AD pathogenesis are discussed. Moreover, our findings warrant further research regarding a possible general and novel interaction between amyloidogenic peptides and other Zn(2+)metallopeptidases with an IDE-like fold and a substrate conformation-dependent recognition mechanism.
de Tullio
Matías B
MB
Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, CONICET, Buenos Aires, Argentina.
Morelli
Laura
L
Castaño
Eduardo M
EM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D014645:Herpesvirus 3, Human / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D011991:Receptors, Virus / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D011991:Receptors, Virus; D007339:Insulysin; D015032:Zinc