The N-terminal Helix Controls the Transition between the Soluble and Amyloid States of an FF Domain

Virginia Castillo, Fabrizio Chiti, Salvador Ventura

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)


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 α-helical structures and their self-assembly into nonnative intermolecular β-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 α-helices into amyloid fibrils using an all-α 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 α-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 α-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 α-helices as a strategy to neutralize such potentially deleterious stretches. © 2013 Castillo et al.
Original languageEnglish
Article numbere58297
JournalPLoS ONE
Issue number3
Publication statusPublished - 7 Mar 2013


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