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

Prion. 2008 Apr-Jun;2(2):51-6. doi: 10.4161/pri.2.2.6710. Epub 2008 May 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Herpesvirus 3, Human / metabolism
  • Humans
  • Insulysin / metabolism*
  • Molecular Chaperones / metabolism*
  • Multiprotein Complexes / metabolism*
  • Protein Binding
  • Receptors, Virus / metabolism
  • Zinc / metabolism

Substances

  • Amyloid beta-Peptides
  • Molecular Chaperones
  • Multiprotein Complexes
  • Receptors, Virus
  • Insulysin
  • Zinc