posted on 2023-11-16, 21:08authored byAmaruka Hazari, Michael R. Sawaya, Maria Sajimon, Niko Vlahakis, Jose Rodriguez, David Eisenberg, Jevgenij A. Raskatov
The rippled β-sheet was theorized
by Pauling and
Corey in
1953 as a structural motif in which mirror image peptide strands assemble
into hydrogen-bonded periodic arrays with strictly alternating chirality.
Structural characterization of the rippled β-sheet was limited
to biophysical methods until 2022 when atomic resolution structures
of the motif were first obtained. The crystal structural foundation
is restricted to four model tripeptides composed exclusively of aromatic
residues. Here, we report five new rippled sheet crystal structures
derived from amyloid β and amylin, the aggregating toxic peptides
of Alzheimer’s disease and type II diabetes, respectively.
Despite the variation in peptide sequence composition, all five structures
form antiparallel rippled β-sheets that extend, like a fibril,
along the entire length of the crystalline needle. The long-range
packing of the crystals, however, varies. In three of the crystals,
the sheets pack face-to-face and exclude water, giving rise to cross-β
architectures grossly resembling the steric zipper motif of amyloid
fibrils but differing in fundamental details. In the other two crystals,
the solvent is encapsulated between the sheets, yielding fibril architectures
capable of host–guest chemistry. Our study demonstrates that
the formation of rippled β-sheets from aggregating racemic peptide
mixtures in three-dimensional (3D) assemblies is a general phenomenon
and provides a structural basis for targeting intrinsically disordered
proteins.