Open AccessThe N-terminal Helix Controls the Transition between the Soluble and Amyloid States of an FF Domain
Author(s) -
Virginia Leyva Castillo,
Fabrizio Chiti,
Salvador Ventura
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0058297
Subject(s) - amyloid (mycology) , fibril , helix (gastropod) , biophysics , protein folding , chemistry , transition (genetics) , protein structure , protein aggregation , amyloid fibril , beta sheet , amyloid disease , protein secondary structure , protein domain , amyloid β , biochemistry , biology , medicine , gene , inorganic chemistry , ecology , disease , pathology , snail
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.