Lipid-mediated Protein Signaling

Jacques Fantini, Nouara Yahi, Fantini, Jacques, Yahi, Nouara

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.