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Vol 47(2013) N 3 p. 440-445; I.A. Popov1,2,3,4,5, M.I. Indeikina1,3,5, A.S. Kononikhin1,5, N.L. Starodubtseva1, S.A. Kozin3,4*, A.A. Makarov3, E.N. Nikolaev1,2,4,5 ESI-MS Identification of the Minimal Zinc-Binding Center in Natural Isoforms of β-Amyloid Domain 1-16 1Talrose Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, 119334 Russia2Moscow Institute of Physics and Technology (State University), Dolgoprudny, 141700 Russia 3Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia 4Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, 119121 Russia 5Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119991 Russia *kozinsa@gmail.com Received - 2012-10-10; Accepted - 2012-10-16 Alzheimer's disease is a lethal neurodegenerative pathology accompanied by the formation of water-soluble neurotoxic oligomers of the human β-amyloid peptide, Aβ, which are then accumulated as polymeric extracellular aggregates (the so-called amyloid plaques). The human Aβ isoform isomerized at aspartate 7 (isoAβ) is the major component of amyloid plaques and is regarded as a potential causative agent for Alzheimer's disease. A mechanism for producing this isoform from a genetically determined variant of D7N β-amyloid (Tottori mutation) has been proposed. However, the rat/mouse Aβ (ratAβ), which carries three amino acid substitutions in metal-binding domain 1-16, is not susceptible to pathogenic aggregation in vivo, unlike the other known genetically determined or chemically modified natural Aβ isoforms. The nteractions with zinc ion play a key role in the in vitro and in vivo aggregation of monomeric human Aβ. Here, we have used high-resolution ESI-MS to demonstrate for the first time that domains 1-16 of the isoforms isoAβ and D7N-Aβ bind zinc ion in exactly the same manner as human 1-16 Aβ domain. On the other hand, the structure of the minimal zinc-binding center in ratAβ differs significantly. These results confirm the general mechanism underlying the interaction of zinc ions with human Aβ isoforms and suggest that structural modulations of Aβ region 6-14 can be used as a promising approach to the therapy of Alzheimer's disease. structure, mechanism, chelation, mass spectrometry, β-amyloid, zinc |