Chapter category: Neurodegenerative Disease
alpha-Synuclein Physiology and Membrane Binding
Chapter authors:
An amphipathic alpha-helical domain in the N-terminus of alpha-synuclein (AS) mediates binding to phospholipid membranes. This domain is structurally similar to the class A2 lipid-binding motif described for the exchangeable apolipoproteins. AS is unstructured in aqueous solution, but shifts to a unique alpha11/3-helical conformation in the presence of phospholipid vesicles or SDS. In addition, AS binds fatty acids, particularly those with long polyunsaturated acyl chains (PUFAs), and these interactions can induce irreversible multimerization of the protein. Biochemically, AS functions as an inhibitor of phospholipases D1 and D2 (PLD1 and PLD2), which catalyze the cleavage of phosphatidylcholine (PC) to generate phosphatidic acid (PA) and free choline. AS also regulates the activity of the plasma membrane dopamine transporter, probably via a mechanism involving internalization and sequestration of the transporter protein. Still other evidence links AS to the maintenance of vesicular pools in the presynapse. This review considers how these distinct functions may relate to the unique membrane interactions of AS, and the significance of such interactions for AS structure and function.
