Rospigliosi, Carla C.McClendon, SebastianSchmid, Adrian W.Ramlall, Trudy F.Barré, PatrickLashuel, Hilal A.Eliezer, David2009-10-282009-10-282009-10-28200910.1016/j.jmb.2009.03.065https://infoscience.epfl.ch/handle/20.500.14299/43940WOS:00026612130000919345692Parkinson's disease (PD) is associated with the deposition of fibrillar aggregates of the protein alpha-synuclein (alphaS) in neurons. Intramolecular contacts between the acidic C-terminal tail of alphaS and its N-terminal region have been proposed to regulate alphaS aggregation, and two originally described PD mutations, A30P and A53T, reportedly reduce such contacts. We find that the most recently discovered PD-linked alphaS mutation E46K, which also accelerates the aggregation of the protein, does not interfere with C-terminal-to-N-terminal contacts and instead enhances such contacts. Furthermore, we do not observe a substantial reduction in such contacts in the two previously characterized mutants. Our results suggest that C-terminal-to-N-terminal contacts in alphaS are not strongly protective against aggregation, and that the dominant mechanism by which PD-linked mutations facilitate alphaS aggregation may be altering the physicochemical properties of the protein such as net charge (E46K) and secondary structure propensity (A30P and A53T).Mutationtext::journal::journal article::research article