+@article{ sandal08,
+ author = MSandal #" and "# FValle #" and "# ITessari #" and "#
+ SMammi #" and "# EBergantino #" and "# FMusiani #" and "#
+ MBrucale #" and "# LBubacco #" and "# BSamori,
+ title = {Conformational Equilibria in Monomeric $\alpha$-Synuclein
+ at the Single-Molecule Level},
+ year = 2008,
+ month = jan,
+ address = {Department of Biochemistry G. Moruzzi,
+ University of Bologna, Bologna, Italy.},
+ journal = PLOS:BIO,
+ volume = 6,
+ number = 1,
+ pages = {e6},
+ issn = {1545-7885},
+ doi = {10.1371/journal.pbio.0060006},
+ url = {http://www.ncbi.nlm.nih.gov/pubmed/18198943},
+ language = {eng},
+ keywords = {Buffers},
+ keywords = {Circular Dichroism},
+ keywords = {Copper},
+ keywords = {Entropy},
+ keywords = {Models, Molecular},
+ keywords = {Molecular Sequence Data},
+ keywords = {Mutation},
+ keywords = {Protein Structure, Secondary},
+ keywords = {Protein Structure, Tertiary},
+ keywords = {alpha-Synuclein},
+ abstract = {Human $\alpha$-Synuclein ($\alpha$Syn) is a natively
+ unfolded protein whose aggregation into amyloid fibrils is
+ involved in the pathology of Parkinson disease. A full
+ comprehension of the structure and dynamics of early intermediates
+ leading to the aggregated states is an unsolved problem of
+ essential importance to researchers attempting to decipher the
+ molecular mechanisms of $\alpha$Syn aggregation and formation of
+ fibrils. Traditional bulk techniques used so far to solve this
+ problem point to a direct correlation between $\alpha$Syn's unique
+ conformational properties and its propensity to aggregate, but
+ these techniques can only provide ensemble-averaged information
+ for monomers and oligomers alike. They therefore cannot
+ characterize the full complexity of the conformational equilibria
+ that trigger the aggregation process. We applied atomic force
+ microscopy-based single-molecule mechanical unfolding methodology
+ to study the conformational equilibrium of human wild-type and
+ mutant $\alpha$Syn. The conformational heterogeneity of monomeric
+ $\alpha$Syn was characterized at the single-molecule level. Three
+ main classes of conformations, including disordered and
+ ``$\beta$-like'' structures, were directly observed and quantified
+ without any interference from oligomeric soluble forms. The
+ relative abundance of the ``$\beta$-like'' structures
+ significantly increased in different conditions promoting the
+ aggregation of $\alpha$Syn: the presence of \Cu, the pathogenic
+ A30P mutation, and high ionic strength. This methodology can
+ explore the full conformational space of a protein at the
+ single-molecule level, detecting even poorly populated conformers
+ and measuring their distribution in a variety of biologically
+ important conditions. To the best of our knowledge, we present
+ for the first time evidence of a conformational equilibrium that
+ controls the population of a specific class of monomeric
+ $\alpha$Syn conformers, positively correlated with conditions
+ known to promote the formation of aggregates. A new tool is thus
+ made available to test directly the influence of mutations and
+ pharmacological strategies on the conformational equilibrium of
+ monomeric $\alpha$Syn.},
+}
+