Assessing the Structural Dynamics and Membrane Interactions of the Disordered Protein Alpha-Synuclein

Abstract

Alpha-Synuclein (aSyn) is a small (140-amino acid), soluble neuronal protein that plays a critical role in Parkinson's Disease (PD). Both its native function and its contribution to the disease state are still incompletely understood at the molecular level. aSyn is intrinsically disordered, displaying little or no secondary structure in solution, although it forms an N-terminal (residues 9 to 93) amphipathic α-helix upon binding to lipid bilayers. Moreover, aSyn can act as a membrane curvature-sensing protein and can remodel lipid membranes to induce high curvature. Here we describe our efforts to understand membrane curvature sensing and generation by aSyn. Using single molecule fluorescence and other techniques, we find that while curvature sensing is generally conserved throughout the membrane binding region of aSyn, curvature generation requires specific binding domains. These results will help to form a model for the interplay between aSyn membrane binding activity and membrane remodeling and may have implications for understanding both aSyn's native role as well as its contribution to PD.