Amyloid-Associated Nucleic Acid Hybridisation

Abstract

Nucleic acids promote amyloid formation in diseases including Alzheimer's and Creutzfeldt-Jakob disease. However, it remains unclear whether the close interactions between amyloid and nucleic acid allow nucleic acid secondary structure to play a role in modulating amyloid structure and function. Here we have used a simplified system of short basic peptides with alternating hydrophobic and hydrophilic amino acid residues to study nucleic acid - amyloid interactions. Employing biophysical techniques including X-ray fibre diffraction, circular dichroism spectroscopy and electron microscopy we show that the polymerized charges of nucleic acids concentrate and enhance the formation of amyloid from short basic peptides, many of which would not otherwise form fibres. In turn, the amyloid component binds nucleic acids and promotes their hybridisation at concentrations below their solution K d, as shown by time-resolved FRET studies. The self-reinforcing interactions between peptides and nucleic acids lead to the formation of amyloid nucleic acid (ANA) fibres whose properties are distinct from their component polymers. In addition to their importance in disease and potential in engineering, ANA fibres formed from prebiotically-produced peptides and nucleic acids may have played a role in early evolution, constituting the first entities subject to Darwinian evolution.

Origin of life. Primordial genetics: Information transfer in a pre-RNA world based on self-replicating beta-sheet amyloid conformers

“…Moreover, oligomers are readily synthesized on certain mineral surfaces (Ferris 1996) and amyloid can spontaneously form fibrillar networks that acts as scaffolds for the amyloid assemblies themselves (Hamley 2007), as well as for other molecules, such as ribonucleotides (Liu et al 2008). Amyloid may also enhance the polymerization of ribonucleotides, and nucleic acids may enhance amyloid formation (Braun et al 2012). Of interest, in the context of the Cairns-Smith´s clay-as-genes hypothesis (Cairns-Smith 1982), is the observation that clay minerals can catalyze the formation of RNA (Wenhua and Ferris 2007).…”

“…Amyloid possesses the propensity to form self-propagating stable fibrillar networks that can act as scaffolds for nucleic acids ( Nandi andNicole 2004, Silva et al 2008) and other molecules, including lipids (Relini et al 2008, Domano andKinnunen 2008). Moreover, the amyloid surface can promote the polymerization of ribonucleotides, and nucleic acids may also enhance amyloidogenesis (Braun et al 2012). Importantly, amyloid-nucleic acid complexes enhance nucleic acid hybridization (Braun et al2012).…”

On the Possible Amyloid Origin of Protein Folds

“…39 Similarly, an amyloid formed from a basic peptide will have a higher affinity for the negatively charged backbone of a DNA molecule than a single peptide. 43 The wide species distribution and growing number of known functional amyloids is further evidence that despite its simplicity, the amyloid fold can give rise to a plethora of activities. 42 Finally, a feature that sets the amyloid structure apart with regard to a CA fold is that it can be formed by peptides as short as four amino acid residues, thus providing small peptides access to some features of larger folded proteins.…”

“…43,61 Interestingly, several studies have shown that there has been an evolutionary selection against β-aggregation-prone In each polymorph, the Glu side chain (yellow) exists in only one of two favored conformations. As in (a), there is an energy barrier (e.g., steric clashes) that prevents an individual from changing conformation on its own.…”

Cooperative induction of ordered peptide and fatty acid aggregates

“…Such mutually beneficial effects have been shown for DNA and peptide amyloids, for which DNA stabilizes the amyloid fibers and the amyloid supports DNA hybridization (12). Furthermore, the encapsulation inside of vesicles by amphiphilic membrane-like structures may be beneficial to the encapsulated system by offering protection from hydrolysis and by preventing loss of the system through diffusion, as has been demonstrated for example by the chemical replication of RNA inside fatty acid vesicles (13) or by protein translation within vesicles that contain the 80 different macromolecular species required for translation (14).…”