Nature and significance of the interactions between amyloid fibrils and biological polyelectrolytes

Year: 2006

Authors: Calamai M., Kumita JR., Mifsud J., Parrini C., Ramazzotti M., Ramponi G., Taddei N., Chiti F., Dobson CM.

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

Abstract: Charged polyelectrolytes such as glycosaminoglycans and nucleic acids have frequently been found associated with the proteinaceous deposits in the tissues of patients with amyloid diseases. We have investigated the nature and generality of this phenomenon by studying the ability of different polyanions, including DNA, ATP, heparin, and heparan sulfate, to promote the aggregation of amyloidogenic proteins and to bind to the resulting aggregates. Preformed amyloid fibrils of human muscle acylphosphatase and human lysozyme, proteins with a net positive charge at physiological pH values, were found to bind tightly to the negatively charged DNA or ATP. The effects of the polyelectrolytes on the kinetics of aggregation were studied for acylphosphatase, and the presence of ATP, DNA, or heparin was found to increase its aggregation rate dramatically, with a degree dependent on the net charge and size of the polyanion. Magnesium or calcium ions were found to attenuate, and ultimately to suppress, these interactions, suggesting that they are electrostatic in nature. Moreover, heparin was found to stabilize the aggregated state of acylphosphatase through compensation of electrostatic repulsion. Noteworthy, differences in affinity between native and aggregated acylphosphatase with heparin suggest that amyloid fibrils can themselves behave as polyelectrolytes, interacting very strongly with other polyelectrolytes bearing the opposite charge. Within an in vivo context, the strengthening of the electrostatic interactions with other biological polyelectrolytes, as a consequence of protein misfolding and aggregation, could therefore result in depletion of essential molecular components and contribute to the known cytotoxicity of amyloid fibrils and their precursors.

Journal/Review: BIOCHEMISTRY

Volume: 45 (42)      Pages from: 12806  to: 12815

KeyWords: Adenosinetriphosphate; Agglomeration; Diseases; Muscle; Nucleic acids; pH effects, Amyloid fibrils; Cytotoxicity; Electrostatic repulsion; Molecular components, Polyelectrolytes, acylphosphatase; adenosine triphosphate; amyloid; calcium ion; DNA; glycosaminoglycan; heparan sulfate; heparin; lysozyme; magnesium ion; nucleic acid; polyelectrolyte, Alzheimer disease; amyloidosis; article; cytotoxicity; DNA binding; electricity; fluorescence; infrared spectroscopy; pH; priority journal; protein aggregation; protein folding; protein purification, Amyloid; Animals; Electrolytes; Heparin; Kinetics; Microfibrils; Microscopy, Fluorescence; Spectrophotometry, Infrared; Spectroscopy, Fourier Transform Infrared; Swine
DOI: 10.1021/bi0610653

Citations: 124
data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2024-07-14
References taken from IsiWeb of Knowledge: (subscribers only)
Connecting to view paper tab on IsiWeb: Click here
Connecting to view citations from IsiWeb: Click here