Depth of α-Synuclein in a Bilayer Determined by Fluorescence, Neutron Reflectometry, and Computation

摘要: α-Synuclein (α-syn) membrane interactions are implicated in the pathogenesis of Parkinson's disease. Fluorescence and neutron reflectometry (NR) measurements reveal that α-syn penetrates ∼9–14 A into outer leaflet bilayer, with a substantial portion membrane-bound polypeptide extending aqueous solvent. For first time, to our knowledge, we used NR obtain direct quantitative evidence α-syn-induced thinning. To examine effect specific residues on penetration depths, series W4-containing N-terminal peptides. We identified 15 (P15) nearly recapitulate features full-length protein (i.e., partition constants, molecular mobility, insertion W4 side chain bilayer), found as few four sufficient for vesicle binding. Although at least one imperfect amphipathic repeat sequence (KAKEGV) is required α-helical formation, secondary structural formation has little affinity. develop an model bilayer interactions, performed molecular-dynamics simulations P15 peptide submerged bilayer. The simulation results highly consistent experimental data indicating broad low-energy region (8.5–14.5 A) insertion.