Molecular interactions of amyloid nanofibrils with biological aggregation modifiers: implications for cytotoxicity mechanisms and biomaterial design

Abstract

Amyloid nanofibrils are ubiquitous biological protein fibrous aggregates, with a wide range of either toxic or beneficial activities that are relevant to human disease and normal biology. Protein amyloid fibrillization occurs via nucleated polymerization, through non-covalent interactions. As such, protein nanofibril formation is based on a complex interplay between kinetic and thermodynamic factors. The process entails metastable oligomeric species and a highly thermodynamically favoured end state. The kinetics, and the reaction pathway itself, can be influenced by third party moieties, either molecules or surfaces. Specifically, in the biological context, different classes of biomolecules are known to act as catalysts, inhibitors or modifiers of the generic protein fibrillization process. The biological aggregation modifiers reviewed here include lipid membranes of varying composition, glycosaminoglycans and metal ions, with a final word on xenobiotic compounds. The corresponding molecular interactions are critically analysed and placed in the context of the mechanisms of cytotoxicity of the amyloids involved in diverse pathologies and the non-toxicity of functional amyloids (at least towards their biological host). Finally, the utilization of this knowledge towards the design of bio-inspired and biocompatible nanomaterials is explored.

Regulation of Functional Protein Aggregation by Multiple Factors: Implications for the Amyloidogenic Behavior of the CAP Superfamily Proteins

“…Pathological aggregates of Aβ42, tau, α-synuclein and PrP induced by GAGs are implicated in neurodegenerative diseases [ 80 ]. GAGs are also able to reduce the cytotoxicity of a number of amyloid systems by different mechanisms [ 81 ]. GAGs-accelerated aggregation can provide protection against the cytotoxicity of intermediate oligomers.…”

A novel amyloid designable scaffold and potential inhibitor inspired by GAIIG of amyloid beta and the HIV‐1 V3 loop

“…Naturally occurring peptide sequences extracted from amyloid proteins or β‐sheet protein regions can self‐assemble outside the context of the entire sequence into amyloid β‐sheets and can serve as scaffolds for novel materials . GAIIGL and NSGAITIG are two peptide sequences similar in sequence which are part of the amyloid‐β (Aβ) peptide, linked to Alzheimer's disease, and the adenovirus fiber shaft , respectively.…”

Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

“…107 The effect of metal ion concentrations on Ab has also been studied extensively, 88 and generally must be considered on a case by case basis since the type of ion and its relative amount (stoichiometry) to Ab can have enormous implications. 108 At concentrations of 100 mM, Cu 2+ and Zn 2+ cause amorphous aggregation of Ab-42. The presence of Cu 2+ , Zn 2+ and Fe 3+ at concentrations of 100 mM increases the volume of aggregated Ab-42 by a signicant percentage.…”