Mutational analysis of the aggregation-prone and disaggregation-prone regions of acylphosphatase

Year: 2009

Authors: Calamai M., Tartaglia GG., Vendruscolo M., Chiti F., Dobson CM.

Autors Affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB21EW, UK;
Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, 50134 Florence, Italy;
Consorzio interuniversitario “Istituto Nazionale Biostrutture e Biosistemi” (I.N.B.B.), Viale delle Medaglie d’Oro, 305, 00136 Rome, Italy

Abstract: We have performed an extensive mutational analysis of aggregation and disaggregation of amyloid-like protofibrils of human muscle acylphosphatase. Our findings indicate that the regions that promote aggregation in 25%, (v/v) 2,2,2 trifluoroethanol (TFE) are different from those that promote disaggregation under milder conditions (5% TFE). Significant changes in the rate of disaggregation of protofibrils in 5% TFE result not only from mutations situated in the regions of the sequence that play a key role in the mechanism of aggregation in 25%, TFE, but also from mutations located in other regions. In order to rationalise these results, we have used a modified version of the Zyggregator aggregation propensity prediction algorithm to take into account structural rearrangements of the protofibrils that may be induced by changes in Solution conditions. Our results suggest that a wider range of residues contributes to the stability of the aggregates in addition to those that play an important kinetic role in the aggregation process. The Mutational approach described here is capable of providing residue-specific information on the structure and dynamics of amyloid protofibrils under conditions close to physiological and should be widely applicable to other systems. (C) 2008 Elsevier Ltd. All rights reserved.

Journal/Review: JOURNAL OF MOLECULAR BIOLOGY

Volume: 387 (4)      Pages from: 965  to: 974

More Information: We are very grateful for Support from the Wellcome Trust, the Royal Society, the Leverhulme Trust, the European Commission (Research Directorates, project HPRN-CT-2002-00241) and the Italian MIUR (FIRM RB\\TE03PX83).
KeyWords: acylphosphatase; amyloid; trifluoroethanol, algorithm; article; dynamics; gene mutation; information; kinetics; mutational analysis; physiology; prediction; priority journal; protein aggregation; protein structure, Acid Anhydride Hydrolases; Algorithms; Amino Acid Substitution; Amyloid; Enzyme Stability; Humans; Models, Molecular; Muscles; Mutagenesis, Site-Directed; Mutation; Protein Folding; Protein Structure, Quaternary; Recombinant Proteins; Spectrometry, Fluorescence; Trifluoroethanol
DOI: 10.1016/j.jmb.2008.09.003

Citations: 10
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