A Tetramer Derived from Islet Amyloid Polypeptide

Aggregation
of the islet amyloid polypeptide (IAPP) to form fibrils
and oligomers is important in the progression of type 2 diabetes.
This article describes X-ray crystallographic and solution-state NMR
studies of peptides derived from residues 11–17 of IAPP that
assemble to form tetramers. Incorporation of residues 11–17
of IAPP (RLANFLV) into a macrocyclic β-sheet peptide results
in a monomeric peptide that does not self-assemble to form oligomers.
Mutation of Arg11 to the uncharged isostere citrulline
gives peptide homologues that assemble to form tetramers in both the
crystal state and in aqueous solution. The tetramers consist of hydrogen-bonded
dimers that sandwich together through hydrophobic interactions. The
tetramers share several features with structures reported for IAPP
fibrils and demonstrate the importance of hydrogen bonding and hydrophobic
interactions in the oligomerization of IAPP-derived peptides.