pH-Driven Polymorphism of Insulin Amyloid-Like Fibrils

Abstract

Prions are infective proteins, which can self-assemble into different strain conformations, leading to different disease phenotypes. An increasing number of studies suggest that prion-like self-propagation may be a common feature of amyloid-like structures. Thus it is important to unravel every possible factor leading to the formation of different amyloid strains. Here we report on the formation of two types of insulin amyloid-like fibrils with distinct infrared spectroscopic features grown under slightly different pH conditions. Similar to prion strains, both insulin fibril types are able to self-propagate their conformational template under conditions, favoring spontaneous formation of different type fibrils. The low-pH-induced insulin amyloid strain is structurally very similar to previously reported strains formed either in the presence of 20% ethanol, or by modification of the amino acid sequence of insulin. A deeper analysis of literature data in the context of our current findings suggests a shift of the monomer-dimer equilibrium of insulin as a possible factor controlling the formation of different strains.

The Environment Is a Key Factor in Determining the Anti-Amyloid Efficacy of EGCG

“…This raises the question as to the origin of such variable results. First, alterations in environmental conditions can modulate protein aggregation pathways and result in the formation of structurally distinct amyloid aggregates ( Figure 6A) [22][23][24]26,27]. Thus, it is plausible that species targeted by the compound might exist only under certain environmental conditions.…”

“…The formation of amyloid fibrils is a complex process, which involves several microscopic steps (e.g., nucleation, growth, fragmentation, and secondary nucleation) [1,2]. Alterations in environmental conditions can modulate these microscopic steps, resulting in different pathways and leading to the formation of structurally distinct amyloid aggregates [1,[22][23][24][25]. Such conformational variability, also known as polymorphism, is thought to be a generic property of amyloid proteins, and has been proposed to be able to cause distinct disease phenotypes [1,26,27].…”

“…Despite its main application in medicine, recombinant human insulin is also extensively used as a model protein to study pathways and mechanisms of amyloid fibril formation in vitro. It has been demonstrated that several sets of conditions, including the presence of ethanol [52][53][54]; different pHs [22,55] or salt concentrations [23,55]; and agitation [55,56], can alter insulin aggregation pathways and even lead to the formation of structurally different amyloid fibrils. The majority of insulin aggregation studies were performed at low pHs, which do not reflect the physiological environment, but serve to significantly accelerate amyloid fibril formation through a destabilisation of the native state.…”

Potential mechanisms and implications for the formation of tau oligomeric strains

“…Within the same disease, some strains may correlate with certain disease stages. There may be diversity by brain region as well as by cell type as different environmental conditions including pH(Sneideris et al , 2015, Verasdonck et al , 2015) and temperature(Tanaka et al , 2006) could lead to conformational changes. The impact of interactions with chaperones, as well as post-translational modifications are also important areas of exploration as the formation of amyloid strains has been shown to depend on variability of chaperone interaction(Sporn and Hines, 2015) and tau is known to interact with a number of different chaperones that affect its aggregation(Petrucelli et al , 2004, Dickey et al , 2006).…”

Revisiting the structure of a synthetic somatostatin analogue for peptide drug design

“…This fact underlines the necessity for further examination of molecular architecture towards exploration of its polymorphism. Development of new (structural and/or crystal) polymorphs of a molecule could be induced by modification of the environmental parameters such as pH, relative humidity, temperature, ion concentration while molecular concentration can also play an important role (Chan et al, 2004;Veesler et al, 2004;Raijada et al, 2010;Fili et al, 2015;Sneideris et al, 2015). Different polymorphs tend to exhibit diverse physicochemical characteristics which are directly linked to their stability as well as their activity profile (Owen et al, 2012;Blandizzi et al, 2015;Censi & Di Martino, 2015).…”