title: The driving force of alpha-synuclein insertion and amyloid channel formation in the plasma membrane of neural cells: key role of ganglioside- and cholesterol-binding domains.
abstract: Alpha-synuclein is an amyloidogenic protein expressed in brain and involved in Parkinson's disease. It is an intrinsically disordered protein that folds into an alpha-helix rich structure upon binding to membrane lipids. Helical alpha-synuclein can penetrate the membrane and form oligomeric ion channels, thereby eliciting important perturbations of calcium fluxes. The study of alpha-synuclein/lipid interactions had shed some light on the molecular mechanisms controlling the targeting and functional insertion of alpha-synuclein in neural membranes. The protein first interacts with a cell surface glycosphingolipid (ganglioside GM3 in astrocytes or GM1 in neurons). This induces the folding of an alpha-helical domain containing a tilted peptide (67-78) that displays a high affinity for cholesterol. The driving force of the insertion process is the formation of a transient OH-Pi hydrogen bond between the ganglioside and the aromatic ring of the alpha-synuclein residue Tyr-39. The higher polarity of Tyr-39 vs. the lipid bilayer forces the protein to cross the membrane, allowing the tilted peptide to reach cholesterol. The tilted geometry of the cholesterol/alpha-synuclein complex facilitates the formation of an oligomeric channel. Interestingly, this functional cooperation between glycosphingolipids and cholesterol presents a striking analogy with virus fusion mechanisms.
authors.affiliation: Faculté des Sciences Saint-Jérôme, Aix Marseille University, Marseille, France. jacques.fantini@univ-amu.fr
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
authors.forename: Nouara
authors.initials: N
authors.lastname: Yahi
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry*; D005679:G(M3) Ganglioside / Q000737:chemistry*; D006801:Humans; D007473:Ion Channels / Q000737:chemistry*; D009474:Neurons / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000502:physiology
chemical_list: D000682:Amyloid; D005679:G(M3) Ganglioside; D007473:Ion Channels; D051844:alpha-Synuclein; D002784:Cholesterol