Insulin degrading enzyme (IDE) is known to play a pivotal role on amyloidogenic peptide degradation but little is known about the changes in the proteolytic activity of the enzyme upon modification of extemal factors. Particularly, although it has been reported that altered ubiquitin concentration and/or hyperinsulinaemia increase the risk of developing Alzheimer's disease (AD), the molecular mechanism involved is unclear. In this work, we study the role that ubiquitin plays on IDE capability of binding and degrading insulin molecules and the obtained results indicate that ubiquitin has an allosteric role for IDE and high ubiquitin levels impair IDE activity. (C) 2008 Elsevier B.V. All rights reserved.