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  • Title: α-Synuclein interactions with phospholipid model membranes: Key roles for electrostatic interactions and lipid-bilayer structure.
    Author: Pirc K, Ulrih NP.
    Journal: Biochim Biophys Acta; 2015 Oct; 1848(10 Pt A):2002-12. PubMed ID: 26119565.
    Abstract:
    α-Synuclein is a small presynaptic protein that is critically implicated in the onset of Parkinson's disease and other neurodegenerative disorders. It has been assumed that the pathogenesis of α-synuclein is associated with its aggregation, while for its physiological function, binding of α-synuclein to the synaptic vesicle membrane appears to be most important. The present study investigated the mechanism of α-synuclein binding to the lipid membrane. Upon binding to negatively charged small unilamellar vesicles consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol in the liquid-crystalline state, α-synuclein undergoes conformational transition from its native unfolded form to an α-helical structure. The positively charged N-terminal part of α-synuclein is likely to be involved in interactions with the negatively charged lipid surface. α-Synuclein did not associate with vesicles consisting of the zwitterionic (neutral) lipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. The data obtained by circular dichroism spectroscopy, fluorescence anisotropy measurements, differential scanning calorimetry, and calcein efflux assays indicate that in addition to electrostatic interactions, hydrophobic interactions are important in the association of α-synuclein with membranes. The mechanism of α-synuclein binding to lipid membranes is primarily dependent on the surface charge density of the lipid bilayer and the phase state of the lipids. We propose that α-synuclein has a lipid ordering effect and thermally stabilises vesicles.
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