E46K Parkinson’s-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein

• Published in: Journal of molecular biology 2009-05, Vol.388 (5), p.1022-1032
• Main Authors: Rospigliosi, Carla C., McClendon, Sebastian, Schmid, Adrian W., Ramlall, Trudy F., Barré, Patrick, Lashuel, Hilal A., Eliezer, David
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; amyloid; E46K; Humans; Mutagenesis, Site-Directed; Mutation; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease - genetics; Parkinson's; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; protein aggregation; Protein Structure, Secondary - genetics; synuclein
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2009.03.065

Parkinson's disease (PD) is associated with the deposition of fibrillar aggregates of the protein α-synuclein (αS) in neurons. Intramolecular contacts between the acidic C-terminal tail of αS and its N-terminal region have been proposed to regulate αS aggregation, and two originally described PD mutations, A30P and A53T, reportedly reduce such contacts. We find that the most recently discovered PD-linked αS 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 αS are not strongly protective against aggregation, and that the dominant mechanism by which PD-linked mutations facilitate αS aggregation may be altering the physicochemical properties of the protein such as net charge (E46K) and secondary structure propensity (A30P and A53T).