Abstract
Amyloid fibrils, crystal-like fibrillar aggregates of proteins associated with various amyloidoses, have the potential to propagate via a prion-like mechanism. Among known methodologies to dissolve preformed amyloid fibrils, acid treatment has been used with the expectation that the acids will degrade amyloid fibrils similar to acid inactivation of protein functions. Contrary to our expectation, treatment with strong acids, such as HCl or H2SO4, of β2-microglobulin (β2m) or insulin actually promoted amyloid fibril formation, proportionally to the concentration of acid used. A similar promotion was observed at pH 2.0 upon the addition of salts, such as NaCl or Na2SO4. Although trichloroacetic acid, another strong acid, promoted amyloid fibril formation of β2m, formic acid, a weak acid, did not, suggesting the dominant role of anions in promoting fibril formation of this protein. Comparison of the effects of acids and salts confirmed the critical role of anions, indicating that strong acids likely induce amyloid fibril formation via an anion-binding mechanism. The results suggest that although the addition of strong acids decreases pH, it is not useful for degrading amyloid fibrils, but rather induces or stabilizes amyloid fibrils via an anion-binding mechanism.
Highlights
One of the most important properties clarified by amyloid formation at an acidic pH is its energetics
If the charge repulsions are shielded by salts through anion binding, they can form amyloid fibrils when the protein concentration is higher than the solubility [14, 15]
In studies of protein folding at an acidic pH, it has been shown with various proteins that the shielding of positive charge repulsion by anion binding results in the formation of a molten globule state, a compact intermediate of protein folding with a significant amount of native-like secondary structures [16,17,18]
Summary
One of the most important properties clarified by amyloid formation at an acidic pH is its energetics. In studies of protein folding at an acidic pH, it has been shown with various proteins that the shielding of positive charge repulsion by anion binding results in the formation of a molten globule state, a compact intermediate of protein folding with a significant amount of native-like secondary structures [16,17,18]. Even if the concentration of an unfolded protein is higher than solubility, the breakdown of supersaturation by agitation or seeding is required to trigger the formation of amyloid fibrils These factors should be important at a neutral pH, the reactions are more complicated because of the native structure that prevents amyloid formation [11, 20]. We summarize various conditions to stabilize or destabilize amyloid fibrils and their mechanisms in order to reduce the potential risks of amyloid fibrils
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