Order and disorder in the physiological membrane binding of α-synuclein

α-Synuclein (αS) is a neuronal protein that localises predominantly at the presynaptic terminals, and whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson's disease. In vivo αS is partitioned between water-soluble and membrane-bound states, and this highly regulated equilibrium influences its biological behaviour under both physiological and pathological conditions. Here we discuss the sequence and structural determinants underlying the transition between the unstructured cytosolic and partially structured membrane-bound states of αS. The balance between order and disorder in this protein system is crucial for the overall regulation of the membrane affinity, the ability to induce the clustering of synaptic vesicles, and the tendency to self assemble into amyloid fibrils at the surface of biological membranes.