Amyloid fibril formation can proceed from different conformations of a partially unfolded protein

Year: 2005

Authors: Calamai M., Chiti F., Dobson CM.

Autors Affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
Dipartimento di Scienze Biochimiche, Universita` degli Studi di Firenze, 50134 Firenze, Italy

Abstract: Protein misfolding and aggregation are interconnected processes involved in a wide variety of nonneuropathic, systemic, and neurodegenerative diseases. More generally, if mutations in sequence or changes in environmental conditions lead to partial unfolding of the native state of a protein, it will often aggregate, sometimes into well-defined fibrillar structures. A great deal of interest has been directed at discovering the characteristic features of metastable partially unfolded states that precede the aggregated states of proteins. In this work, human muscle acylphosphatase (AcP) has been first destabilized, by addition of urea or by means of elevated temperatures, and then incubated in the presence of different concentrations of 2,2,2, trifluoroethanol ranging from 5% to 25% (v/v). The results show that AcP is able to form both fibrillar and non fibrillar aggregates with a high beta-sheet content from partially unfolded states with very different structural features. Moreover, the presence of alpha-helical structure in such a state does not appear to be a fundamental determinant of the ability to aggregate. The lack of ready aggregation under some of the conditions examined here is attributable primarily to the intrinsic properties of the solutions rather than to specific structural features of the partially unfolded states that precede aggregation. Aggregation appears to be favored when the solution conditions promote stable intermolecular interactions, particularly hydrogen bonds. In addition, the structures of the resulting aggregates are largely independent of the conformational properties of their soluble precursors.

Journal/Review: BIOPHYSICAL JOURNAL

Volume: 89 (6)      Pages from: 4201  to: 4210

KeyWords: acylphosphatase; amyloid; trifluoroethanol; urea, alpha helix; article; beta sheet; degenerative disease; hydrogen bond; molecular interaction; neuropathy; protein aggregation; protein conformation; protein folding; protein structure; systemic disease
DOI: 10.1529/biophysj.105.068726

Citations: 135
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