Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases

Year: 2002

Authors: Chiti F., Calamai M., Taddei N., Stefani M., Ramponi G., Dobson CM.

Autors Affiliation: Dipartimento di Scienze Biochimiche, Universita` degli Studi di Firenze, Viale Morgagni 50, 50134 Florence, Italy; and Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom

Abstract: Protein aggregation and the formation of highly insoluble amyloid structures is associated with a range of debilitating human conditions, which include Alzheimer’s disease, Parkinson’s disease, and the Creutzfeldt-Jakob disease. Muscle acylphosphatase (AcP) has already provided significant insights into mutational changes that modulate amyloid formation. In the present paper, we have used this system to investigate the effects of mutations that modify the charge state of a protein without affecting significantly the hydrophobicity or secondary structural propensities of the polypeptide chain. A highly significant inverse correlation was found to exist between the rates of aggregation of the protein variants under denaturing conditions and their overall net charge. This result indicates that aggregation is generally favored by mutations that bring the net charge of the protein closer to neutrality. In light of this finding, we have analyzed natural mutations associated with familial forms of amyloid diseases that involve alteration of the net charge of the proteins or protein fragments associated with the diseases. Sixteen mutations have been identified for which the mechanism of action that causes the pathological condition is not yet known or fully understood. Remarkably, 14 of these 16 mutations cause the net charge of the corresponding peptide or protein that converts into amyloid deposits to be reduced. This result suggests that charge has been a key parameter in molecular evolution to ensure the avoidance of protein aggregation and identifies reduction of the net charge as an important determinant in at least some forms of protein deposition diseases.

Journal/Review: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Volume: 99 (Suppl 4)      Pages from: 16419  to: 16426

KeyWords: acylphosphatase; mutant protein, Alzheimer disease; amyloidosis; conference paper; Creutzfeldt Jakob disease; gene mutation; hydrophobicity; in vitro study; Parkinson disease; priority journal; protein aggregation; protein conformation; protein denaturation; protein secondary structure; protein stability
DOI: 10.1073/pnas.212527999

Citations: 246
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