title: A novel mechanism of interaction between alpha-synuclein and biological membranes.
abstract: Conformational abnormalities and aggregation of alpha-synuclein (alpha-syn) have been linked to the pathogenesis of Parkinson's (PD) and related diseases. It has been shown that alpha-syn can stably bind artificial phospholipid vesicles through alpha-helix formation in its N-terminal repeat region. However, little is known about the membrane interaction in cells. In the current study, we determined the membrane-binding properties of alpha-syn to biological membranes by using bi-functional chemical crosslinkers, which allow the detection of transient, but specific, interactions. By utilizing various point mutations and deletions within alpha-syn, we demonstrated that the membrane interaction of alpha-syn in cells is also mediated by alpha-helix formation in the N-terminal repeat region. Moreover, the PD-linked A30P mutation causes reduced membrane binding, which is concordant with the artificial membrane studies. However, contrary to the interaction with artificial membranes, the interaction with biological membranes is rapidly reversible and is not driven by electrostatic attraction. Furthermore, the interaction of alpha-syn with cellular membranes occurs only in the presence of non-protein and non-lipid cytosolic components, which distinguishes it from the spontaneity of the interaction with artificial membranes. More interestingly, addition of the cytosolic preparation to artificial membranes resulted in the transient, charge-independent binding of alpha-syn similar to the interaction with biological membranes. These results suggest that in cells, alpha-syn is engaged in a fundamentally different mode of membrane interaction than the charge-dependent artificial membrane binding, and the mode of interaction is determined by the intrinsic properties of alpha-syn itself and by the cytoplasmic context.
authors.affiliation: The Parkinson's Institute, Sunnyvale, CA 94089, USA.
authors.forename: Yoon Suk
authors.initials: YS
authors.lastname: Kim
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Laurine
authors.forename: Wendy
authors.initials: W
authors.lastname: Woods
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003432:Cross-Linking Reagents; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D008567:Membranes, Artificial; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D051381:Rats; D012965:Sodium Chloride / Q000494:pharmacology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D008563:Membrane Lipids; D008567:Membranes, Artificial; D051844:alpha-Synuclein; D012965:Sodium Chloride