Nucleic acid-mediated protein aggregation and assembly

Abstract

Amyloid proteins, mainly including amyloid-β peptides, prion proteins, α-synuclein, copper/zinc superoxide dismutase, as well as the bacterial protein RepA, are characterized by the deposition in a variety of tissues or cells as aggregated species (amyloids or insoluble deposits or inclusions) that share a distinctive β-sheet-rich fibrillar ultrastructure. Although the amyloid is predominantly proteinaceous, careful examination of disease tissues and cells has revealed the presence of a significant quantity of polyanionic species including nucleic acids and polysaccharides associated with the amyloid. For example, in the brain tissues from victims of Alzheimer's disease, nucleic acids have been detected in neurofibrillary tangles and intracellular inclusions primarily composed of the tau protein, as well as in senile plaques composed of the amyloid-β peptides. Therefore, much effort has been directed to understanding the roles of the ubiquitous polyanionic species such as nucleic acids in the aggregation of amyloid proteins. Increasing evidence indicates that the amyloid proteins exhibit a high binding affinity for nucleic acids and the binding is mainly driven by electrostatic interactions between both. The association with nucleic acids leads to significant variations of the amyloid proteins in conformation. The nucleic acids have been observed to be capable of significantly inducing and accelerating the aggregation of amyloid proteins likely through a template effect. The template effect could restrict the orientations of amyloid proteins along nucleic acid strands and increase the local concentrations of amyloid proteins on nucleic acid surfaces, leading to enhancement in the intermolecular hydrophobic contacts of amyloid proteins. The nucleic acids have also been found to occur as an intrinsic or transient component in the resulted proteinaceous aggregates.