Evidence for copper-dioxygen reactivity during alpha-synuclein fibril formation.
Alpha-synuclein (alpha-syn), a presynaptic protein implicated in Parkinson's disease, binds copper(II) ion (1:1) with submicromolar affinity in vitro. Insights on the molecular details of soluble- and fibrillar-Cu-alpha-syn are gained through X-ray absorption spectroscopy. Our results indicate that the copper coordination environment (3-to-4 N/O ligands, average Cu-ligand distance approximately 1.96 A) exhibits little structural rearrangement upon amyloid formation in spite of the overall polypeptide conformational change from disordered-to-beta-sheet. Interestingly, we find that some population of Cu(II)-alpha-syn reduces to Cu(I)-alpha-syn in the absence of O(2). This autoreduction event appears diminished in the presence of O(2) suggestive of preceding Cu(I)/O(2) chemistry. Evidence for generation of reactive oxygen species is obtained by the observation of new emission features attributed to dityrosine cross-links in fibrillar samples.
Lucas
Heather R
HR
Laboratory of Molecular Biophysics and Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Debeer
Serena
S
Hong
Myoung-Soon
MS
Lee
Jennifer C
JC
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D012995:Solubility; D013050:Spectrometry, Fluorescence; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
D051844:alpha-Synuclein; D003300:Copper; D010100:Oxygen