Parkinson's disease is a neurodegenerative disease that affects approximately 1% of people over the age of 60. In the rapidly aging population of the Western world, this represents an increasingly heavy social and economic burden. Along with related synucleinopathies, Parkinson's disease is genetically and pathologically linked to the presynaptic protein alpha-synuclein, which aggregates in intraneuronal Lewy bodies in patients. Aside from its interaction with synaptic vesicles, which implicates alpha-synuclein in regulation of synaptic vesicle exocytosis, the normal function of this protein is not well understood. In dilute aqueous solution, alpha-synuclein contains no stable secondary or tertiary structure, making it a member of the class of intrinsically disordered proteins; however, much of alpha-synuclein undergoes a disorder-to-helix transition when binding to lipid membranes. Alpha-synuclein is also post-translationally modified in vivo, in the form of ubiquitous and permanent N-terminal amine acetylation and transient phosphorylation on several serine and tyrosine residues. How these modifications play into the role of alpha-synuclein is also unclear. The effects of N-terminal acetylation and phosphorylation of tyrosines 39 and 125 on alpha-synuclein structure in the free state were assessed using NMR and CD spectroscopy, as were the effects on binding to synthetic lipid vesicles and membrane-mimetic detergent micelles. N-terminal acetylation increases helicity at the very N-terminus of alpha-synuclein in the free state; this effect propagates into the membrane-bound state, with the acetylated protein displaying stabilized helicity at the N-terminus and tighter binding to more curved lipid vesicles with lower, more physiologically-relevant proportions of negatively-charged lipids, similar to synaptic vesicles. The modified protein binds to ?-octyl-glucoside micelles in a previously unknown, partly helical conformation that may serve as a model for in vitro studies of pathogenic intermediates. In contrast, phosphorylation at tyrosine 39 has minor effects on the disordered state but greatly perturbs the lipid-bound protein, with the C-terminal half of the lipid-binding domain detaching from the membrane. This phosphorylation event may thus control rearrangements of alpha-synuclein molecules bound to membrane surfaces at the synapse, and play an important role in the native function of alpha-synuclein, knowing which is key to making progress in understanding Parkinson's disease.