The N-terminus of α-synuclein is essential for both monomeric and oligomeric interactions with membranes

The intrinsically disordered protein alpha-synuclein (alpha SN) is linked to Parkinson's Disease and forms both oligomeric species and amyloid fibrils. The N-terminal part of monomeric aSN interacts strongly with membranes and alpha SN cytotoxicity has been attributed to oligomers' ability to interact with and perturb membranes. We show that membrane folding of monomeric wt alpha SN and N-terminally truncated variants correlates with membrane permeabilization. Further, the first 11 N-terminal residues are crucial for monomers' and oligomers' interactions with and permeabilization of membranes. We attribute oligomer permeabilization both to cooperative electrostatic interactions through the N-terminus and interactions mediated by hydrophobic regions in the oligomer. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.