The N-terminal helix controls the transition between the soluble and amyloid states of an FF domain.

PloS one

PubMedID: 23505482

Castillo V, Chiti F, Ventura S. The N-terminal helix controls the transition between the soluble and amyloid states of an FF domain. PLoS ONE. 2013;8(3):e58297.
BACKGROUND
Protein aggregation is linked to the onset of an increasing number of human nonneuropathic (either localized or systemic) and neurodegenerative disorders. In particular, misfolding of native a-helical structures and their self-assembly into nonnative intermolecular ß-sheets has been proposed to trigger amyloid fibril formation in Alzheimer's and Parkinson's diseases.

METHODS
Here, we use a battery of biophysical techniques to elucidate the conformational conversion of native a-helices into amyloid fibrils using an all-a FF domain as a model system.

RESULTS
We show that under mild denaturing conditions at low pH this FF domain self-assembles into amyloid fibrils. Theoretical and experimental dissection of the secondary structure elements in this domain indicates that the helix 1 at the N-terminus has both the highest a-helical and amyloid propensities, controlling the transition between soluble and aggregated states of the protein.

CONCLUSIONS
The data illustrates the overlap between the propensity to form native a-helices and amyloid structures in protein segments.

SIGNIFICANCE
The results presented contribute to explain why proteins cannot avoid the presence of aggregation-prone regions and indeed use stable a-helices as a strategy to neutralize such potentially deleterious stretches.