Many intrinsically-unstructured-proteins are involved, through their aggregation into amyloid fibrils, in neuro-degenerative pathologies like Parkinson’s, Alzheimer’s and prion diseases. The process of aggregation is still poorly understood because traditional bulk methods can only provide ensemble-averaged information for monomers and oligomers alike. These limitations can be circumvented by the novel AFM-based single-molecule approach we have recently developed to study the conformational equilibria of these proteins (1,2). This methodology proved very effective in characterizing the conformational diversity of wild type (WT) alpha-synuclein and we observed that in several unrelated conditions linked to the pathogenicity of Parkinson’s disease the conformational equilibrium of this protein shifts toward beta-sheet-containing structures. The direct relationship of these beta-structures to alpha-synuclein toxicity was confirmed by our single-molecule study of the conformational heterogeneity of its pathologic mutants A30P, A53T and E46K. (2)

Conformational equilibria of intrinsically disordered proteins probed by single molecule methodologies

SAMORI', BRUNO
2009

Abstract

Many intrinsically-unstructured-proteins are involved, through their aggregation into amyloid fibrils, in neuro-degenerative pathologies like Parkinson’s, Alzheimer’s and prion diseases. The process of aggregation is still poorly understood because traditional bulk methods can only provide ensemble-averaged information for monomers and oligomers alike. These limitations can be circumvented by the novel AFM-based single-molecule approach we have recently developed to study the conformational equilibria of these proteins (1,2). This methodology proved very effective in characterizing the conformational diversity of wild type (WT) alpha-synuclein and we observed that in several unrelated conditions linked to the pathogenicity of Parkinson’s disease the conformational equilibrium of this protein shifts toward beta-sheet-containing structures. The direct relationship of these beta-structures to alpha-synuclein toxicity was confirmed by our single-molecule study of the conformational heterogeneity of its pathologic mutants A30P, A53T and E46K. (2)
Summer School "PHYSICS AND CHEMISTRY IN NANOBIOTECHNOLOGY" http://www.isf.univpm.it/jesi2009/
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Samorì B.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/84596
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