Conformational equilibria in monomeric alpha-synuclein at the single molecule level

Details Conformational equilibria in monomeric alpha-synuclein at the single molecule level Conformational equilibria in monomeric alpha-synuclein at the single molecule level

2007-12-12

arxiv.org/abs/0712.1973v1

Biology

Quantitative Biology

Biomolecules

37 pages, 9 figures (including supplementary material)

Scientific paper

Natively unstructured proteins defy the classical "one sequence-one structure" paradigm of protein science. Monomers of these proteins in pathological conditions can aggregate in the cell, a process that underlies socially relevant neurodegenerative diseases such as Alzheimer and Parkinson. A full comprehension of the formation and structure of the so-called misfolded intermediates from which the aggregated states ensue is still lacking. We characterized the folding and the conformational diversity of alpha-synuclein (aSyn), a natively unstructured protein involved in Parkinson disease, by mechanically stretching single molecules of this protein and recording their mechanical properties. These experiments permitted us to directly observe directly and quantify three main classes of conformations that, under in vitro physiological conditions, exist simultaneously in the aSyn sample, including disordered and "beta-like" structures. We found that this class of "beta-like" structures is directly related to aSyn aggregation. In fact, their relative abundance increases drastically in three different conditions known to promote the formation of aSyn fibrils: the presence of Cu2+, the occurrence of the pathogenic A30P mutation, and high ionic strength. We expect that a critical concentration of aSyn with a "beta-like" structure must be reached to trigger fibril formation. This critical concentration is therefore controlled by a chemical equilibrium. Novel pharmacological strategies can now be tailored to act upstream, before the aggregation process ensues, by targeting this equilibrium. To this end, Single Molecule Force Spectroscopy can be an effective tool to tailor and test new pharmacological agents.

Affiliated with

Also associated with

No associations

Rating

Conformational equilibria in monomeric alpha-synuclein at the single molecule level does not yet have a rating. At this time, there are no reviews or comments for this scientific paper.

If you have personal experience with Conformational equilibria in monomeric alpha-synuclein at the single molecule level, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Conformational equilibria in monomeric alpha-synuclein at the single molecule level will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFWR-SCP-O-661790