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The role of amino acid side chain oxidation in the formation of amyloid assemblies has been investigated. Chemical oxidation of amino acid side chains has been used as a facile method of introducing mutations on pro-tein structures. Oxidation promotes changes within tertiary contacts that enable identification of residues and interactions critical in stabilizing pro-tein structures. | ễFEBS Journal Oxidation inhibits amyloid fibril formation of transthyretin Simin D. Maleknia1 Natalia Reixach2 and Joel N. Buxbaum2 1 Schoolof Biological Earth and EnvironmentalSciences University of New South Wales Sydney NSW Australia 2 Division of Rheumatology Research Department of Molecular and ExperimentalMedicine Scripps Research Institute La Jolla CA USA Keywords amyloid fibril footprinting radical probe mass spectometry reactive oxygen species transthyretin Correspondence S. D. Maleknia Schoolof Biological Earth and EnvironmentalSciences University of New South Wales Sydney NSW 2052 Australia E-mail s.maleknia@unsw.edu.au Received 11 July 2006 revised 28 September 2006 accepted 9 October 2006 doi 10.1111 j.1742-4658.2006.05532.x The role of amino acid side chain oxidation in the formation of amyloid assemblies has been investigated. Chemical oxidation of amino acid side chains has been used as a facile method of introducing mutations on protein structures. Oxidation promotes changes within tertiary contacts that enable identification of residues and interactions critical in stabilizing protein structures. Transthyretin TTR is a soluble human plasma protein. The wild-type WT and several of its variants are prone to fibril formation which leads to amyloidosis associated with many clinical syndromes. The effects of amino acid side chain oxidations were investigated by comparing the kinetics of fibril formation of oxidized and unoxidized proteins. The WT and V30M TTR mutant valine 30 substituted with methionine were allowed to react over a time range of 10 min to 12 h with hydroxy radical and other reactive oxygen species. In these timescales up to five oxygen atoms were incorporated into WT and V30M TTR proteins. Oxidized proteins retained their tetrameric structures as determined by cross-linking experiments. Side chain modification of methionine residues at position 13 and 30 the latter for V30M TTR only were dominant oxidative products. Mono-oxidized and .
