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

• Published in: FEBS letters 2014-01, Vol.588 (3), p.497-502
• Main Authors: Lorenzen, Nikolai, Lemminger, Lasse, Pedersen, Jannik Nedergaard, Nielsen, Søren Bang, Otzen, Daniel Erik
• Format: Article
• Language: English
• Subjects: 1-anilinonaphthalene-8-sulfonate; A4F; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Amyloid - chemistry; Amyloid - metabolism; Amyloid - ultrastructure; ANS; asymmetrical flow field-flow fractionation; Cell Membrane Permeability - genetics; circular dichroism; DLS; dynamic light scattering; Humans; Hydrophobic and Hydrophilic Interactions; Membrane folding; Membrane interaction; Membranes - chemistry; Membranes - ultrastructure; Oligomer; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's Disease; Permeabilization; Protein Multimerization; Protein Structure, Quaternary; SDS; SEC; size exclusion chromatography; sodium dodecyl sulfate; Static Electricity; thioflavin T; ThT; Toxicity; α-synuclein; αSN
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2013.12.015

•We have analyzed the membrane interactions of α-synuclein monomers and oligomers.•Different N-terminal deletion mutants have been compared.•The first 11 N-terminal residues are essential for this membrane interaction.•Membrane folding correlates with membrane permeabilization and toxicity.•Oligomers bind to membranes by electrostatic and hydrophobic interactions. The intrinsically disordered protein α-synuclein (αSN) is linked to Parkinson’s Disease and forms both oligomeric species and amyloid fibrils. The N-terminal part of monomeric αSN interacts strongly with membranes and αSN cytotoxicity has been attributed to oligomers’ ability to interact with and perturb membranes. We show that membrane folding of monomeric wt αSN 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.