The study investigates how α-synuclein, a presynaptic protein linked to Parkinson's and Alzheimer's diseases, stabilizes its secondary structure when bound to synthetic membranes. α-Synuclein, which is highly conserved and contains repetitive 11-residue sequences, is hypothesized to associate with phospholipid bilayers, stabilizing its α-helical structure. Experiments show that α-synuclein binds to small unilamellar vesicles (SUV) containing acidic phospholipids but not to vesicles with neutral charge. This binding increases α-helicity from 3% to approximately 80%, suggesting a role in vesicle function at the presynaptic terminal. α-Synuclein is also the precursor to a component of extracellular plaques in Alzheimer's disease and is found in intracellular inclusions (Lewy bodies) in Parkinson's disease. The protein's sequence contains amphipathic α-helical domains, similar to those in apolipoproteins, which may facilitate lipid binding. However, unlike apolipoproteins, α-synuclein binds exclusively to acidic phospholipids and preferentially to smaller vesicles. These findings suggest that the protein's secondary structure may target it to specific vesicles in the presynaptic terminal, potentially regulating vesicle function. Circular dichroism measurements confirmed that lipid binding significantly increases α-helicity in α-synuclein. Structural analysis revealed that α-synuclein contains five amphipathic α-helical domains, with helices 1–4 resembling class A2 amphipathic α-helices. Helix 5 resembles class G* helices, which are less well defined. These structural features may explain α-synuclein's ability to bind to acidic phospholipids and its potential role in lipid and protein interactions. The study also highlights the importance of lipid composition and curvature in α-synuclein binding. α-Synuclein binds more strongly to smaller, curved SUVs than to larger, planar large unilamellar vesicles (LUVs). This suggests that α-synuclein may be involved in regulating vesicle function at the presynaptic terminal. The findings provide insights into the structural and functional properties of α-synuclein, its interactions with lipid membranes, and its potential role in neurodegenerative diseases.The study investigates how α-synuclein, a presynaptic protein linked to Parkinson's and Alzheimer's diseases, stabilizes its secondary structure when bound to synthetic membranes. α-Synuclein, which is highly conserved and contains repetitive 11-residue sequences, is hypothesized to associate with phospholipid bilayers, stabilizing its α-helical structure. Experiments show that α-synuclein binds to small unilamellar vesicles (SUV) containing acidic phospholipids but not to vesicles with neutral charge. This binding increases α-helicity from 3% to approximately 80%, suggesting a role in vesicle function at the presynaptic terminal. α-Synuclein is also the precursor to a component of extracellular plaques in Alzheimer's disease and is found in intracellular inclusions (Lewy bodies) in Parkinson's disease. The protein's sequence contains amphipathic α-helical domains, similar to those in apolipoproteins, which may facilitate lipid binding. However, unlike apolipoproteins, α-synuclein binds exclusively to acidic phospholipids and preferentially to smaller vesicles. These findings suggest that the protein's secondary structure may target it to specific vesicles in the presynaptic terminal, potentially regulating vesicle function. Circular dichroism measurements confirmed that lipid binding significantly increases α-helicity in α-synuclein. Structural analysis revealed that α-synuclein contains five amphipathic α-helical domains, with helices 1–4 resembling class A2 amphipathic α-helices. Helix 5 resembles class G* helices, which are less well defined. These structural features may explain α-synuclein's ability to bind to acidic phospholipids and its potential role in lipid and protein interactions. The study also highlights the importance of lipid composition and curvature in α-synuclein binding. α-Synuclein binds more strongly to smaller, curved SUVs than to larger, planar large unilamellar vesicles (LUVs). This suggests that α-synuclein may be involved in regulating vesicle function at the presynaptic terminal. The findings provide insights into the structural and functional properties of α-synuclein, its interactions with lipid membranes, and its potential role in neurodegenerative diseases.