Molecular basis for amyloid fibril formation and stability

TLDR

The molecular structure of amyloid fibrils has remained elusive due to challenges in obtaining well‑diffracting crystals. High‑resolution (1 Å) electron and X‑ray diffraction of engineered polypeptide crystals enabled detailed amyloid structure determination. The crystal structure shows antiparallel β‑sheet cross‑β architecture stabilized by π‑bonding between phenylalanine rings and glutamic acid–lysine salt bridges, highlighting key interactions that likely govern amyloid formation and stability.

Abstract

The molecular structure of the amyloid fibril has remained elusive because of the difficulty of growing well diffracting crystals. By using a sequence-designed polypeptide, we have produced crystals of an amyloid fiber. These crystals diffract to high resolution (1 Å) by electron and x-ray diffraction, enabling us to determine a detailed structure for amyloid. The structure reveals that the polypeptides form fibrous crystals composed of antiparallel β-sheets in a cross-β arrangement, characteristic of all amyloid fibers, and allows us to determine the side-chain packing within an amyloid fiber. The antiparallel β-sheets are zipped together by means of π-bonding between adjacent phenylalanine rings and salt-bridges between charge pairs (glutamic acid–lysine), thus controlling and stabilizing the structure. These interactions are likely to be important in the formation and stability of other amyloid fibrils.