Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes

Abstract

Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The molecular mechanism of toxicity is under intense debate, as many hypotheses concerning the involvement of the amyloid and the toxic oligomers have been proposed. However, the main role is represented by the interplay of protein and the cell membrane. Thus, the understanding of the interaction mechanism at the molecular level is crucial to shed light on the dynamics driving this phenomenon. There are plenty of factors influencing the interaction as mentioned above, however, the overall view is made trickier by the apparent irreproducibility and inconsistency of the data reported in the literature. Here, we contextualized this topic in a historical, and even more importantly, in a future perspective. We introduce two novel insights: the chemical equilibrium, always established in the aqueous phase between the free and the membrane phospholipids, as mediators of protein-transport into the core of the bilayer, and the symmetry-breaking of oligomeric aggregates forming an alternating array of partially ordered and disordered monomers.

Interactions of Viral Proteins from Pathogenic and Low or Non-Pathogenic Orthohantaviruses with Human Type I Interferon Signaling

“…In addition, the analysis of the NSs amino acid sequences with the PONDR software (Figure 4c) showed that the NSs of low and non-pathogenic viruses, TULV, and PHV displayed a higher level of disordering than PUUV-NSs protein in the N-ter region containing the NoLS. Of note, protein disordering is a feature that is usually associated to a high capacity of interaction [41,42]. The NoLS corresponding regions of TULV and PHV possess a polar motif positively charged, KRR 16-18 and NGR 16-18 respectively, while, in the PUUV NSs protein, different polar residues with positive and negative charges were found in the corresponding region, REQ [16][17][18] , as shown by alignment of the NSs protein sequences (Figure 4d).…”

Secondary Structures of Proteins: A Comparison of Models and Experimental Results

“… 1 Wild type (WT) and A53T α-synucleins (α-Ss) are the second system, which is involved in Parkinson’s disease. 2 The A53T mutation in α-synuclein is related to autosomal-dominant early onset familial Parkinson’s disease. 3 All of these proteins are intrinsically disordered proteins (IDPs) 4 , 5 that have no single well-defined tertiary structure under native conditions.…”

Membrane Interactions and Toxicity by Misfolded Protein Oligomers

“…Protein oligomers have been shown to induce higher levels of cellular toxicity than mature fibrils. This has been consistently observed in many protein systems including Aβ (Walsh et al, 2002) and tau (Ward Sarah et al, 2012) in AD, αSyn (Winner et al, 2011) in PD and human islet amyloid polypeptide (IAPP) in type II diabetes (Abedini et al, 2016;Scollo and La Rosa, 2020). Compared to mature fibrils, protein oligomers have specific molecular structural characteristics that enhance their ability to induce neurotoxicity, including small size (Mannini et al, 2014), exposure of hydrophobic surfaces (Vivoli Vega et al, 2019) and unsaturated edge-strands (De Simone et al, 2008).…”