Structural Role of Compensatory Aminoacid Replacements in the Alpha - Synuclein Protein

2 MD studies of the protein in micelles point to a lower degree of flexibility of huAS(A53T) with respect to the huAS(wt) (39). MD studies of the protein in lipid bilayer provide also interesting insights on the wild type structures, suggesting in particular that the truncated protein (residues 1–95) forms a bent helix due to its collective motions (40), and that the truncated fragment (residues 31−52) assumes a high degree of conformational disorder (41). 3 NMR has provided insights of the protein in the solid state at 263 K (42). mAS(wt) was found to lose transient contacts C/NAC and C/N-terminal contacts. The N-terminal domain was more rigid and the NAC region more solvent exposed relative to that of huAS(wt). Abstract A subset of familial Parkinson's Disease (PD) cases is associated with the presence of disease-causing point mutations in human α-synuclein (huAS(wt)), including A53T. Surprisingly, the human neurotoxic aminoacid 53T is present in non-primate, wild-type sequences of α-synucleins, including that expressed by mice (mAS(wt)). Since huAS(A53T) causes neurodegeneration when expressed in rodents, the aminoacid changes between the wild-type human protein (huAS(wt)) and mAS(wt) might act as intramolecular suppressors of A53T toxicity in the mouse protein, restoring its physiological structure and function. The lack of structural information for mAS(wt) in aqueous solution has prompted us to carry out a comparative molecular dynamics study of huAS(wt), huAS(A53T) and mAS(wt) in water at 300 K. The calculations are based on an ensemble of NMR-derived huAS(wt) structures. huAS(A53T) turns out to be more flexible and less compact than huAS(wt). Its central (NAC) region, involved in the fibril formation of the protein, is more solvent-exposed than that of the wild-type protein, in agreement with NMR data. The compactness of mAS(wt) is similar to that of the human protein. In addition, its NAC region is less solvent-exposed and more rigid than that of huAS(A53T). All of these facets may be caused by an increase of intramolecular interactions on passing from huAS(A53T) to mAS(wt). We conclude that the presence of 'compensatory replacements' in the mouse protein causes a significant change of the protein relative to huAS(A53T), restoring features not too dissimilar to those of the human protein. 4 Parkinson's disease (PD) is a neurodegenerative disease affecting about five million people worldwide (1). In post-mortem brains of sporadic PD patients, proteinaceous fibrillar aggregates, called Lewy bodies, represent the neuropathological hallmark of the disease. The major components of Lewy bodies …