Pre-structured hydrophobic peptide β-strands: A universal amyloid trap?

Abstract

Amyloid fibril formation has long been studied because of the variety of proteins that are capable of adopting this structure despite sharing little sequence homology. This makes amyloid fibrils a challenging focus for inhibition studies because the peptides and proteins that form amyloid fibrils cannot be targeted based on a sequence motif. Most peptide inhibitors that target specific amyloidogenic proteins rely heavily on sequence recognition to ensure that the inhibitory peptide is able to bind its target. This approach is limited to targeting one amyloidogenic protein at a time. However, there is increasing evidence of cross-reactivity between amyloidforming polypeptides. It has therefore become more useful to study the similarities between these proteins that goes beyond their sequence homology. Indeed, the observation that amyloidogenic proteins adopt similar secondary structures along the pathway to fibril formation opens the way to an interesting investigation: the development of inhibitors that could be universal amyloid traps. The review below will analyze two specific amyloidogenic proteins, α-synuclein and human amylin, and introduce a small number of peptides that have been shown to be capable of inhibiting the amyloidogenesis of both of these very dissimilar polypeptides. Some of the inhibitory peptide motifs may indeed, be applicable to Aβ and other amyloidogenic systems.

The hot sites of α-synuclein in amyloid fibril formation

“…5a). The regions of (14-18), (35)(36)(37)(38)(39)(40)(41)(42), (46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57), (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80), and (90-94) were identified as chameleon sites with a high tendency for beta structure. These regions are the most likely to form the β-strands in αβT.…”

“…5c shows hydrophobicity values averaged over the sliding windows. The regions of (6-7), (16)(17), (37)(38)(39)(40), (49)(50)(51)(52)(53), (66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76), and (87-93) with values over 0 were identified as hydrophobic sites of αS. These hydrophobic regions are at the heart of hot sites and make them more potent for the formation of amyloid fibrils.…”

“…Therefore, the space is defined by the first three s and conformations are clustered into three clusters. The clustering was performed using the peak-picking algorithm to identify isolated peaks distributed in principal components of the configurations along the TMD trajectories, corresponding to discrete clusters 50 . According to Fig.…”

“…In this study, a comparison was found for monomeric αβT of αS in different conditions using TMD simulations. In the transition pathway, critical sites with a key role in the amyloid fibril formation were identified in three priorities (i) (35)(36)(37)(38)(39)(40)(41)(42)(43) and (47)(48)(49)(50)(51)(52)(53)(54)(55), (ii) (65-75), and (iii) (83-90), respectively. The regions with good overlap, as well as with aggregation-prone regions have been introduced by Pawar et al 51 .…”

Alternative Causal Link between Peptide Fibrillization and β-Strand Conformation

“…For this reason, peptide fragments taking β-strand conformation have also been regarded as the essential motif for self-assembly in many SAP systems. 9 − 11 …”