Alpha-Synuclein, an Intrinsically Unstructured Protein. How Interesting Can It Be?

Abstract

N-terminal acetylation of alpha-synuclein (aS), a 140-residue protein implicated in the etiology of Parkinson's disease, is common in mammals. The impact of this modification on the protein's structure and dynamics in free solution and on its membrane binding properties has been evaluated by both NMR and CD spectroscopy. While in contrast to literature reports, no tetrameric form of acetylated aS could be isolated, N-terminal acetylation resulted in ca 15% transient population of alpha-helical structure for its first six residues. The 1H, 15N, and 13C chemical shifts for residues 13-140 remain unaffected by acetylation. Nevertheless, a substantial increase in affinity of aS for negatively charged lipid membranes is observed, likely to be of strong functional significance. A new method for residue-specific NMR probing of lipid binding is demonstrated for aS and assigns a new putative function to this enigmatic protein. Although free aS in the absence of lipids has backbone chemical shifts that are exceptionally close to random coil values, considerable positional variation for the distribution of its backbone torsion angles and the time scale of local reorientation can be deduced from its 3JHH and NOE data.