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

Raimon Sabaté, Alba Espargaró, Natalia S. de Groot, Juan José Valle-Delgado, Xavier Fernàndez-Busquets, Salvador Ventura

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37 Citations (Scopus)

Abstract

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. © 2010 Elsevier Ltd.
Original languageEnglish
Pages (from-to)337-352
JournalJournal of Molecular Biology
Volume404
DOIs
Publication statusPublished - 26 Nov 2010

Keywords

  • Amyloid formation
  • Islet amyloid polypeptide
  • Protein aggregation
  • Protein sequence
  • Retro proteins

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