Document Detail


Phosphorylation of α-Synuclein at Y125 and S129 alters its metal binding properties: implications for understanding the role of α-Synuclein in the pathogenesis of Parkinson's Disease and related disorders.
MedLine Citation:
PMID:  22860160     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
α-Synuclein (α-syn) is a 140-amino acid protein that plays a central role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. However, the molecular determinants that are responsible for triggering and/or propagating α-syn aggregation and toxicity remain poorly understood. Several studies have suggested that there are direct interactions between different metals and α-syn, but the role of metal ions and α-syn in the pathogenesis of PD is not firmly established. Interestingly, the majority of disease-associated post-translational modifications (PTMs) (e.g., truncation, phosphorylation, and nitration) of α-syn occur at residues within the C-terminal region (Y125, S129, Y133, and Y136) and in very close proximity to the putative metal binding sites. Therefore, we hypothesized that phosphorylation within this domain could influence the α-syn-metal interactions. In this paper, we sought to map the interactions between the di- and trivalent cations, Cu(II), Pb(II), Fe(II), and Fe(III), and the C-terminal region of α-syn encompassing residues 107-140 and to determine how phosphorylation at S129 or Y125 alters the specificity and binding affinity of metals using electrospray ionization-mass spectrometry (ESI-MS) and fluorescence spectroscopy. We demonstrate that D115-M116 and P128-S129 act as additional Cu(II) binding sites and show for the first time that the residues P128-S129 and D119 are also involved in Pb(II) and Fe(II) coordination, although D119 is not essential for binding to Fe(II) and Pb(II). Furthermore, we demonstrate that phosphorylation at either Y125 or S129 increases the binding affinity of Cu(II), Pb(II), and Fe(II), but not Fe(III). Additionally, we also show that phosphorylations at these residues lead to a shift in the binding sites of metal ions from the N-terminus to the C-teminus. Together, our findings provide critical insight into and expand our understanding of the molecular and structural bases underlying the interactions between α-syn and metal ions, including the identification of novel metal binding sites, and highlight the potential importance of cross-talk between post-translational modifications and metal ion binding in modulating α-syn functional and aggregation properties that are regulated by its C-terminal domain.
Authors:
Yu Lu; Michel Prudent; Bruno Fauvet; Hilal A Lashuel; Hubert H Girault
Publication Detail:
Type:  Journal Article     Date:  2011-09-14
Journal Detail:
Title:  ACS chemical neuroscience     Volume:  2     ISSN:  1948-7193     ISO Abbreviation:  ACS Chem Neurosci     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2012-08-03     Completed Date:  2013-04-04     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101525337     Medline TA:  ACS Chem Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  667-75     Citation Subset:  IM    
Affiliation:
Laboratoire d'Electrochimie Physique et Analytique, Station 6, Ecole Polytechnique Fédérale de Lausane, CH-1015 Lausanne, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Binding Sites
Copper / metabolism
Cross-Linking Reagents
Fluorescence
Humans
Iron / metabolism
Lead / metabolism
Metals / metabolism*
Models, Molecular
Molecular Sequence Data
Neuropeptides / chemical synthesis,  chemistry
Parkinson Disease / metabolism*,  pathology
Phosphorylation
Spectrometry, Mass, Electrospray Ionization
Tandem Mass Spectrometry
Tyrosine / chemistry,  metabolism
alpha-Synuclein / chemistry*
Chemical
Reg. No./Substance:
0/Cross-Linking Reagents; 0/Metals; 0/Neuropeptides; 0/alpha-Synuclein; 55520-40-6/Tyrosine; 7439-89-6/Iron; 7439-92-1/Lead; 7440-50-8/Copper
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