Designed peptides that assemble into cross-α amyloid-like structures

Amyloids adopt 'cross-beta' structures composed of long, twisted fibrils with beta-strands running perpendicular to the fibril axis. Recently, a toxic peptide was proposed to form amyloid-like cross-alpha structures in solution, with a planar bilayer-like assembly observed in the crystal structure. Here we crystallographically characterize designed peptides that assemble into spiraling cross-alpha amyloid-like structures, which resemble twisted beta-amyloid fibrils. The peptides form helical dimers, stabilized by packing of small and apolar residues, and the dimers further assemble into cross-alpha amyloid-like fibrils with superhelical pitches ranging from 170 angstrom to 200 angstrom. When a small residue that appeared critical for packing was converted to leucine, it resulted in structural rearrangement to a helical polymer. Fluorescently tagged versions of the designed peptides form puncta in mammalian cells, which recover from photobleaching with markedly different kinetics. These structural folds could be potentially useful for directing in vivo protein assemblies with predetermined spacing and stabilities.