The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S |
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| Authors: | Diego Sbardella Grazia R. Tundo Andrea Coletta Julien Marcoux Efthymia Ioanna Koufogeorgou Chiara Ciaccio Anna M. Santoro Danilo Milardi Giuseppe Grasso Paola Cozza Marie-Pierre Bousquet-Dubouch Stefano Marini Massimo Coletta |
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| Affiliation: | 1.Department of Clinical Sciences and Translational Medicine,University of Roma Tor Vergata,Rome,Italy;2.Interuniversitary Center for the Research on the Chemistry of Metals in Biological Systems,Bari,Italy;3.Interdepartmental Center for TeleInfrastructures,University of Roma Tor Vergata,Rome,Italy;4.Department of Chemistry,Aarhus University,Aarhus,Denmark;5.Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS,Toulouse,France;6.Institute of Biostructures and Bioimaging,National Research Council,Catania,Italy;7.Department of Chemistry,University of Catania,Catania,Italy |
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| Abstract: | The interaction of insulin-degrading enzyme (IDE) with the main intracellular proteasome assemblies (i.e, 30S, 26S and 20S) was analyzed by enzymatic activity, mass spectrometry and native gel electrophoresis. IDE was mainly detected in association with assemblies with at least one free 20S end and biochemical investigations suggest that IDE competes with the 19S in vitro. IDE directly binds the 20S and affects its proteolytic activities in a bimodal fashion, very similar in human and yeast 20S, inhibiting at (IDE)?≤?30 nM and activating at (IDE)?≥?30 nM. Only an activating effect is observed in a yeast mutant locked in the “open” conformation (i.e., the α-3ΔN 20S), envisaging a possible role of IDE as modulator of the 20S “open”–”closed” allosteric equilibrium. Protein–protein docking in silico proposes that the interaction between IDE and the 20S could involve the C-term helix of the 20S α-3 subunit which regulates the gate opening of the 20S. |
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