Binding of alpha-synuclein with Fe(III) and with Fe(II) and biological implications of the resultant complexes.
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.
Peng
Yong
Y
Department of Chemistry and Biochemistry, California State University, Los Angeles, CA 90032, USA.
Wang
Chengshan
C
Xu
Howard H
HH
Liu
You-Nian
YN
Zhou
Feimeng
F
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*
D005290:Ferric Compounds; D005296:Ferrous Compounds; D016877:Oxidants; D051844:alpha-Synuclein; D006861:Hydrogen Peroxide