Calcium-Triggered Membrane Interaction of the -Synuclein Acidic Tail

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• 作者：Shiori Tamamizu-Kato ; Malathi G. Kosaraju ; Hiroyuki Kato ; Vincent Raussens ; Jean-Marie Ruysschaert ; Vasanthy Narayanaswami
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：September 12, 2006
• 年：2006
• 卷：45
• 期：36
• 页码：10947 - 10956
• 全文大小：271K
• 年卷期：v.45,no.36(September 12, 2006)
• ISSN：1520-4995

文摘

-Synuclein (-syn) is a 140-residue protein that aggregates in intraneuronal inclusions calledLewy bodies in Parkinson's disease (PD). It is composed of an N-terminal domain with a propensity tobind lipids and a C-terminal domain rich in acidic residues (the acidic tail). The objective of this studywas to examine the effect of Ca²⁺ on the acidic tail conformation in lipid-bound -syn. We exploit theextreme sensitivity of the band III fluorescence emission peak of the pyrene fluorophore to the polarityof its microenvironment to monitor subtle conformational response of the -syn acidic tail to Ca²⁺. Usingrecombinant human -syn bearing a pyrene to probe either the N-terminal domain or the acidic tail, wenoted that lipid binding resulted in an increase in band III emission intensity in the pyrene probe taggingthe N-terminal domain but not that in the acidic tail. This suggests that the protein is anchored to the lipidsurface via the N-terminal domain. However, addition of Ca²⁺ caused an increase in band III emissionintensity in the pyrene tagging the acidic tail, with a corresponding increased susceptibility to quenchingby quenchers located in the lipid milieu, indicative of lipid interaction of this domain. Taken togetherwith the increased -sheet content of membrane-associated -syn in the presence of Ca²⁺, we propose amodel wherein initial lipid interaction occurs via the N-terminal domain, followed by a Ca²⁺-triggeredmembrane association of the acidic tail as a potential mechanism leading to -syn aggregation. Theseobservations have direct implications in the role of age-related oxidative stress and the attendant cellularCa²⁺ dysregulation as critical factors in -syn aggregation in PD.