title: Binding of alpha-synuclein with Fe(III) and with Fe(II) and biological implications of the resultant complexes.
abstract: Parkinson's disease (PD) is hallmarked by the abnormal intracellular inclusions (Lewy bodies or LBs) in dopaminergic cells. Amyloidogenic protein alpha-synuclein (alpha-syn) and iron (including both Fe(III) and Fe(II)) are both found to be present in LBs. The interaction between iron and alpha-syn might have important biological relevance to PD etiology. Previously, a moderate binding affinity between alpha-syn and Fe(II) (5.8x10(3)M(-1)) has been measured, but studies on the binding between alpha-syn and Fe(III) have not been reported. In this work, electrospray mass spectrometry (ES-MS), cyclic voltammetry (CV), and fluorescence spectroscopy were used to study the binding between alpha-syn and Fe(II) and the redox property of the resultant alpha-syn-Fe(II) complex. The complex is of a 1:1 stoichiometry and can be readily oxidized electrochemically and chemically (by O(2)) to the putative alpha-syn-Fe(III) complex, with H(2)O(2) as a co-product. The reduction potential was estimated to be 0.025V vs. Ag/AgCl, which represents a shift by -0.550V vs. the standard reduction potential of the free Fe(III)/Fe(II) couple. Such a shift allows a binding constant between alpha-syn and Fe(III), 1.2x10(13)M(-1), to be deduced. Despite the relatively high binding affinity, alpha-syn-Fe(III) generated from the oxidation of alpha-syn-Fe(II) still dissociates due to the stronger tendency of Fe(III) to hydrolyze to Fe(OH)(3) and/or ferrihydrite gel. The roles of alpha-syn and its interaction with Fe(III) and/or Fe(II) are discussed in the context of oxidative stress, metal-catalyzed alpha-syn aggregation, and iron transfer processes.
authors.affiliation: Department of Chemistry and Biochemistry, California State University, Los Angeles, CA 90032, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.forename: Chengshan
authors.initials: C
authors.lastname: Wang
authors.forename: Howard H
authors.initials: HH
authors.lastname: Xu
authors.forename: You-Nian
authors.initials: YN
authors.lastname: Liu
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
mesh_terms: D000368:Aged; D055664:Electrochemical Techniques; D005290:Ferric Compounds / Q000737:chemistry / Q000378:metabolism*; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016631:Lewy Bodies / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D005290:Ferric Compounds; D005296:Ferrous Compounds; D016877:Oxidants; D051844:alpha-Synuclein; D006861:Hydrogen Peroxide