Electrostatic Complementarity Drives Amyloid/Nucleic Acid Co‐Assembly

Abstract

Proteinaceous plaques associated with neurodegenerative diseases contain many biopolymers including the polyanions glycosaminoglycans and nucleic acids. Polyanion‐induced amyloid fibrillation has been implicated in disease etiology, but structural models for amyloid/nucleic acid co‐assemblies remain limited. Here we constrain nucleic acid/peptide interactions with model peptides that exploit electrostatic complementarity and define a novel amyloid/nucleic acid co‐assembly. The structure provides a model for nucleic acid/amyloid co‐assembly as well as insight into the energetic determinants involved in templating amyloid assembly.

Liquid‐Like Phases Preorder Peptides for Supramolecular Assembly

“…[1][2]4] In disease, polymorphism is prevalent in the assembled amyloid structures, [5] suggesting that multiple nuclei may appear within the disordered phase. Such diversity may underlie the ability of external templates [6] as diverse as nucleic acids [7] to rapidly nucleate the propagation of distinct assemblies from these peptide-rich liquid phases. [6a,8] To explore how these intermediate liquid-like phases might pre-order peptide nucleation, we sought metastable particle phases accessible to detailed spectroscopic structural analyses.…”

“…This detected population of single peptide β-sheets in twostep nucleation events [19] could also respond to environmental templates, ranging from metals, [12,13] nucleic acids, [7] chemical reactions of the peptides, [6a] as well as other peptide assemblies, [6b,8b, f,g,10-11,20] each nucleating the growth of new assemblies. The generality of this model will now be further explored in the context of other intrinsically disordered protein domains [21] and in full-length prions where the range of stable nuclei could be much greater.…”

From Interaction to Function in DNA‐Templated Supramolecular Self‐Assemblies

“…Very recently, Lynn and co‐workers have also reported a study showing how such salt‐bridge interactions could explain the role of nucleic acids in facilitating the growth of amyloid assemblies . In a different topic, Herrmann and co‐workers have shown how such salt‐bridge interactions can be used for preparing PEGylated DNA supramolecular complexes that are able to hybridize in salt‐free water .…”

Supramolecular Architectures of Nucleic Acid/Peptide Hybrids

“…Conversely, the polyanionic property of nucleic acid can, in turn, afford a means of controlling the nucleation of the peptide self-assembly, which might be involved in polyanion-induced amyloid fibrillation that is associated with the corresponding diseases. For example, Lyn and coworkers recently succeeded to obtain high-resolution structural information on the self-assembled nanostructures of a positively charged peptide (Ac-KLVIIAG-NH 2 : 7 aa) that was templated by nucleic acids, which was facilitated by the structural complementarity between the nucleic acid backbone and the antiparallel cross-β structures of the peptides for electrostatic interactions [ 111 ].…”