Abstract:
:Alpha-synuclein (alpha-syn) is a 140-residue protein that aggregates in intraneuronal inclusions called Lewy bodies in Parkinson's disease (PD). It is composed of an N-terminal domain with a propensity to bind lipids and a C-terminal domain rich in acidic residues (the acidic tail). The objective of this study was to examine the effect of Ca(2+) on the acidic tail conformation in lipid-bound alpha-syn. We exploit the extreme sensitivity of the band III fluorescence emission peak of the pyrene fluorophore to the polarity of its microenvironment to monitor subtle conformational response of the alpha-syn acidic tail to Ca(2+). Using recombinant human alpha-syn bearing a pyrene to probe either the N-terminal domain or the acidic tail, we noted that lipid binding resulted in an increase in band III emission intensity in the pyrene probe tagging the N-terminal domain but not that in the acidic tail. This suggests that the protein is anchored to the lipid surface via the N-terminal domain. However, addition of Ca(2+) caused an increase in band III emission intensity in the pyrene tagging the acidic tail, with a corresponding increased susceptibility to quenching by quenchers located in the lipid milieu, indicative of lipid interaction of this domain. Taken together with the increased beta-sheet content of membrane-associated alpha-syn in the presence of Ca(2+), we propose a model wherein initial lipid interaction occurs via the N-terminal domain, followed by a Ca(2+)-triggered membrane association of the acidic tail as a potential mechanism leading to alpha-syn aggregation. These observations have direct implications in the role of age-related oxidative stress and the attendant cellular Ca(2+) dysregulation as critical factors in alpha-syn aggregation in PD.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Tamamizu-Kato S,Kosaraju MG,Kato H,Raussens V,Ruysschaert JM,Narayanaswami Vdoi
10.1021/bi060939isubject
Has Abstractpub_date
2006-09-12 00:00:00pages
10947-56issue
36eissn
0006-2960issn
1520-4995journal_volume
45pub_type
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