Copper(I) and Copper(II) Inhibit A beta Peptides Proteolysis by Insulin-Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer's Disease
Copper(I) and Copper(II) Inhibit A beta Peptides Proteolysis by Insulin-Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer's Disease(763 views) Grasso G, Pietropaolo A, Spoto G, Pappalardo G, Tundo GR, Ciaccio C, Coletta M, Rizzarelli E
Chemistry (ISSN: 0947-6539, 1521-3765, 1521-3765electronic), 2011 Feb 25; 17(9): 2752-2762.
Dipartimento di Scienze Chimiche, Universita di Catania, Catania, Italy.
Istituto Biostrutture e Bioimmagini, CNR, Viale A. Doria 6, 95125, Catania, Italy
Consorzio I. N. B. B., Viale delle Medaglie d'Oro 305, 00136, Roma, Italy
Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, 00133 Roma, Italy
Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, Via C. Ulpiani 27, 70126 Bari, Italy
References: Not available.
Copper(I) and Copper(II) Inhibit A beta Peptides Proteolysis by Insulin-Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer's Disease
Accumulation of neurotoxic amyloid-beta peptide (Abeta) and alteration of metal homeostasis (metallostasis) in the brain are two main factors that have been very often associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Abeta is constantly produced from the amyloidprecursor-protein APP precursor and immediately catabolized under normal conditions, whereas dysmetabolism of Abeta and/or metal ions seems to lead to a pathological deposition. Although insulin-degrading enzyme (IDE) is the main metalloprotease involved in Abeta degradation in the brain being up-regulated in some areas of AD brains, the role of IDE for the onset and development of AD is far from being understood. Moreover, the biomolecular mechanisms involved in the recognition and interaction between IDE and its substrates are still obscure. In spite of the important role of metals (such as copper, aluminum, and zinc), which has brought us to propose a "metal hypothesis of AD", a targeted study of the effect of metallostasis on IDE activity has never been carried out. In this work, we have investigated the role that various metal ions (i. e., Cu (2+), Cu (+), Zn (2+), Ag (+), and Al (3+)) play in modulating the interaction between IDE and two Abeta peptide fragments, namely Abeta (1-16) and Abeta (16-28). It was therefore possible to identify the direct effect that such metal ions have on IDE structure and enzymatic activity without interferences caused by metal-induced substrate modifications. Mass spectrometry and kinetic studies revealed that, among all the metal ions tested, only Cu (2+), Cu (+), and Ag (+) have an inhibitory effect on IDE activity. Moreover, the inhibition of copper (II) is reversed by adding zinc (II), whereas the monovalent cations affect the enzyme activity irreversibly. The molecular basis of their action on the enzyme is also discussed on the basis of computational investigations. Copyright 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Copper(I) and Copper(II) Inhibit A beta Peptides Proteolysis by Insulin-Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer's Disease
Copper(I) and Copper(II) Inhibit A beta Peptides Proteolysis by Insulin-Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer's Disease
Kállay C, Dávid A, Timári S, Nagy EM, Sanna D, Garribba E, Micera G, De Bona P, Pappalardo G, Rizzarelli E, Sóvágó I * Copper(II) complexes of rat amylin fragments(659 views) Dalton T (ISSN: 1477-9234, 1477-9226, 1477-9234electronic), 2011 Oct 14; 40(38): 9711-9721. Impact Factor:3.838 ViewExport to BibTeXExport to EndNote