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

Abstract

Structural studies of amyloidogenic segments by X-ray crystallography have revealed a novel packing motif, consisting of out-of-register β sheets, that 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 β sheets as a common structural motif in amyloid aggregates.

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity

“…Within each sheet, the β-strands form two distinct, unequal interfaces: a stronger interface with twelve hydrogen bonds, and a weaker interface with eight hydrogen bonds (Figure 4B). This inequality between interfaces has been observed in previous examples of out-of-register sheets (Soriaga et al, 2015; Laganowsky et al, 2012; Liu et al, 2012; Yu et al, 2015). A view down the ‘proto-fibril axis’ of the crystal shows that the faces of adjacent sheets are wet and overlap only partially (Figure 4C); the asymmetric unit contains density for seven ordered water molecules and one thiocyanate molecule.…”

“…The β-sheets of the 19–29 S20G atomic structure possess a curvature that is not common in shorter hIAPP protein segments (Wiltzius et al, 2008, 2009a; Soriaga et al, 2015). To assess β-sheet curvature, we compared the root mean square deviations (RMSD’s) of sheets from planarity across all hIAPP protein segment atomic structures determined to date (Supplementary file 1).…”

“…If fibrils are a bona fide type of toxic aggregate in vivo, then determining the atomic structure of the spine of hIAPP fibrils is a logical approach for advancing our understanding of disease-relevant targets (Wiltzius et al, 2008, 2009a; Soriaga et al, 2016). Furthermore, we can utilize atomic structures as templates for structure-based design of novel therapeutics that may protect against pancreatic β-cell death.…”

Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

“…The β-sheets in hIAPP19–29 fibrils was found to have parallel alignment of β-strands using Micro-Electron Diffraction (MicroED) 36 . The antiparallel β-sheets were observed in fibrils of hIAPP23–29 58 and hIPP22–29 59 in other experiments. In (KLVFFAE) n -(NFGAILS) n simulations, the antiparallel β-strands were the dominant conformation (with a probability ~ 0.7–0.8) due to the antiparallel alignment preference among Aβ16–22 peptides and between Aβ16–22 and IAPP22–28 (Fig.…”

Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2

“…In the first model, termed segmental polymorphism, the segment forming the zipper spine differs between amyloid fibrils 21,22 . Segmental polymorphism has been observed in a number of proteins, including islet amyloid polypeptide (IAPP), in which various six- and eleven-residue segments of IAPP are each capable of forming zippers independently 23,24 . In a second model, termed packing polymorphism, a single zipper-forming segment packs differently in different amyloid fibrils 21,22 .…”