Residual structure and dynamics in Parkinson's disease-associated mutants of alpha-synuclein.
alpha-Synuclein (alpha S) is a pre-synaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson's disease (PD). Two autosomal dominant missense mutations in the alpha S gene are associated with early onset PD. Because alpha S is found in an aggregated fibrillar form in the Lewy body deposits characteristic of Parkinson's patients, aggregation of the protein is believed to be related to its involvement in the disease process. The wild type (WT) and early onset mutants A30P and A53T display diverse in vitro aggregation kinetics even though the gross physicochemical and morphological properties of the mutants are highly similar. We used high resolution solution NMR spectroscopy to compare the structural and dynamic properties of the A53T and A30P mutants with those of WT alpha S in the free state. We found that the A30P mutation disrupts a region of residual helical structure that exists in the WT protein, whereas the A53T mutation results in a slight enhancement of a small region around the site of mutation with a preference for extended conformations. Based on these results and on the anticipated effects of these mutations on elements of secondary structure, we proposed a model of how these two PD-linked mutations influence alpha S fibril formation that is consistent with the documented differences in the fibrillization kinetics of the two mutants.
Bussell
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Department of Physiology, Biophysics, and Molecular Medicine Weill Medical College of Cornell University, New York, New York 10021, USA.
Eliezer
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D006801:Humans; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000378:metabolism*; D017433:Protein Structure, Secondary; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein