The Role of Protein Sequence and Amino Acid Composition in Amyloid Formation: Scrambling and Backward Reading of IAPP Amyloid Fibrils

The specific functional structure of natural proteins is determined by the way in which amino acids are sequentially connected in the polypeptide. The tight sequence/structure relationship governing protein folding does not seem to apply to amyloid fibril formation because many proteins without any sequence relationship have been shown to assemble into very similar β-sheet-enriched structures. Here, we have characterized the aggregation kinetics, seeding ability, morphology, conformation, stability, and toxicity of amyloid fibrils formed by a 20-residue domain of the islet amyloid polypeptide (IAPP), as well as of a backward and scrambled version of this peptide. The three IAPP peptides readily aggregate into ordered, β-sheet-enriched, amyloid-like fibrils. However, the mechanism of formation and the structural and functional properties of aggregates formed from these three peptides are different in such a way that they do not cross-seed each other despite sharing a common amino acid composition. The results confirm that, as for globular proteins, highly specific polypeptide sequential traits govern the assembly pathway, final fine structure, and cytotoxic properties of amyloid conformations.

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► Wild-type, scrambled, and backward versions of the IAPP 10–29 domain all form amyloids.
► The amyloidogenic pathways of the wild-type, scrambled, and backward versions of the IAPP 10–29 domain are different.
► The amyloid structures formed by the wild-type, scrambled, and backward versions of the IAPP 10–29 domain differ in stability, conformation, and cytotoxicity.