Structural Polymorphs Suggest Competing Pathways for the Formation of Amyloid Fibrils That Diverge from a Common Intermediate Species

Biochemistry. 2018 Nov 20;57(46):6470-6478. doi: 10.1021/acs.biochem.8b00997. Epub 2018 Nov 6.

Abstract

It is now recognized that many amyloid-forming proteins can associate into multiple fibril structures. Here, we use two-dimensional infrared spectroscopy to study two fibril polymorphs formed by human islet amyloid polypeptide (hIAPP or amylin), which is associated with type 2 diabetes. The polymorphs exhibit different degrees of structural organization near the loop region of hIAPP fibrils. The relative populations of these polymorphs are systematically altered by the presence of macrocyclic peptides which template β-sheet formation at specific sections of the hIAPP sequence. These experiments are consistent with polymorphs that result from competing pathways for fibril formation and that the macrocycles bias hIAPP aggregation toward one pathway or the other. Another macrocyclic peptide that matches the loop region but extends the lag time leaves the relative populations of the polymorphs unaltered, suggesting that the branching point for structural divergence occurs after the lag phase, when the oligomers convert into seeds that template fibril formation. Thus, we conclude that the structures of the polymorphs stem from restricting oligomers along diverging folding pathways, which has implications for drug inhibition, cytotoxicity, and the free energy landscape of hIAPP aggregation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amylin Receptor Agonists / chemistry*
  • Amyloid / chemistry*
  • Humans
  • Islet Amyloid Polypeptide / chemistry*
  • Protein Conformation*
  • Spectrophotometry, Infrared

Substances

  • Amylin Receptor Agonists
  • Amyloid
  • Islet Amyloid Polypeptide