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E46K Parkinson's-linked mutation enhances C-terminal-to-N-terminal contacts in alpha-synuclein.
- Source :
-
Journal of molecular biology [J Mol Biol] 2009 May 22; Vol. 388 (5), pp. 1022-32. Date of Electronic Publication: 2009 Apr 05. - Publication Year :
- 2009
-
Abstract
- Parkinson'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).
- Subjects :
- Humans
Mutagenesis, Site-Directed
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments chemistry
Peptide Fragments genetics
Peptide Fragments metabolism
alpha-Synuclein metabolism
Mutation
Parkinson Disease genetics
Protein Structure, Secondary genetics
alpha-Synuclein chemistry
alpha-Synuclein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1089-8638
- Volume :
- 388
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 19345692
- Full Text :
- https://doi.org/10.1016/j.jmb.2009.03.065