Insight into conformational modification of alpha-synuclein in the presence of neuronal whole cells and of their isolated membranes

•α-Syn interaction to SH-SY5Y cells is accompanied by an increase in α-helical content.•α-Syn N-terminus is involved in the interaction with membrane phospholipids.•Crosslinking experiments in the presence of cells indicate α-Syn monomeric state.•α-Syn retains flexibility and assumes low secondary structure contents. A change in the conformational plasticity of α-Synuclein (α-Syn) is hypothesised to be a key step in the pathogenic mechanism of Parkinson’s disease (PD). Here, we report the study of extracellular α-Syn interaction with whole cells and membranes isolated from the neuronal SH-SY5Y cells, exploiting NMR and CD spectroscopies. In addition, the crosslinking agent DSG was used to freeze the conformational and oligomeric state of α-Syn in the presence of cells. These data, in a quasi-physiological environment, confirm the protein monomeric state with a propensity to adopt a transient alpha helical following interaction with biological membranes.