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 amyloid-forming 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.

Keywords: Amylin; Amyloid; Inhibitors; Parkinson's disease; Synuclein; Type II diabetes.

Graphical abstract

Fig. 1

A schematic drawing depicting the stages of amyloidogenesis as well as the ways different inhibitors can act on this process. The dashed lines indicate hydrogen bonding between monomers. A soluble oligomer phase (*) has been put forth as the most toxic form of misfolded amyloid proteins in a number of cases.

Fig. 2

A) The sequence of αS. The N-terminal region is shown in green, the NAC region is shown in black and the C-terminal region is shown in blue. B) Final form adopted by αS monomers in amyloid fibrils as proposed by Vialr et al. [5] More recent cryo-EM studies of the protofilament stage of αS amymloidogenesis suggest that αS forms polymorphic structures that may have more than 5 β-strands. The strands β1 and β2 of αS have been underlined in A) and highlighted in B) because of the growing interest in this region as a possible pre-amyloid secondary structure formed by αS on the path to amyloid fibril formation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

A) The sequence of human amylin. B) Final form adopted by human amylin monomers in amyloid fibrils. The residues 18–27 of hAM are highlighted in blue in both A) and B) because of the conflicting observations that on the one hand studies show that this is the minimum sequence of hAM capable of forming amyloid fibrils and yet on the other there are indications that in the final amyloid configuration this region has no β-sheet character, rather, it seems to exist as an unstructured loop. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

A schematic drawing showing the secondary structure of some peptides that show inhibition against α-synuclein. WW2 and cyclo WW2 also show potential as universal amyloid traps since they also show activity against hAM.