The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme: A biological perspective

Insulin-degrading enzyme (IDE) is a conserved Zn²⁺metalloendopeptidase involved in insulin degradation and in the maintenance of brain steady-state levels of amyloid β peptide (Aβ) of Alzheimer''s disease (AD). Our recent demonstration that IDE and Aβ 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 Aβ 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 Zn²⁺metallopeptidases with an IDE-like fold and a substrate conformation-dependent recognition mechanism.Key words: amyloid, insulin-degrading enzyme, peptides, alzheimer''s disease, irreversible binding, metalloproteases