Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing

Amyloid fibrils are assemblies of misfolded proteins and are associated wit h pathological conditions such as Alzheimer's disease and the spongiform en cephalopathies, In the amyloid diseases, a diverse group of normally solubl e proteins self-assemble to form insoluble fibrils, X-ray fibre diffraction studies have shown that the protofilament cores of fibrils formed from the various proteins all contain a cross-beta-scaffold, with beta-strands perp endicular and beta-sheets parallel to the fibre axis. We have determined th e three-dimensional structure of an amyloid fibril, formed by the SH3 domai n of phosphatidylinositol-3'-kinase, using cryo-electron microscopy and ima ge processing at 25 Angstrom resolution. The structure is a double helix of two protofilament pairs wound around a hollow core, with a helical crossov er repeat of similar to 600 Angstrom and an axial subunit repeat of similar to 27 Angstrom. The native SH3 domain is too compact to fit into the fibri l density, and must unfold to adopt a longer, thinner shape in the amyloid form. The 20x40-Angstrom protofilaments can only accommodate one pair of fl at beta-sheets stacked against each other, with very little inter-strand tw ist. We propose a model for the polypeptide packing as a basis for understa nding the structure of amyloid fibrils in general.