Crystal Structures of IAPP Amyloidogenic Segments Reveal a Novel Packing Motif of Out-of-Register Beta Sheets

Structural studies of amyloidogenic segments by X-ray crystallography have revealed a novel packing motif, consisting of out-of-register beta sheets, which may constitute one of the toxic species in aggregation related diseases. Here we sought to determine the presence of such a motif in islet amyloid polypeptide (IAPP), whose amyloidogenic properties are associated with type 2 diabetes. We determined four new crystal structures of segments within IAPP, all forming steric zippers. Most interestingly, one of the segments in the fibril core of IAPP forms an out-of-register steric zipper. Analysis of this structure reveals several commonalities with previously solved out-of-register fibrils. Our results provide additional evidence of out of-register beta sheets as a common structural motif in amyloid aggregates.