The protofilament substructure of amyloid fibrils

Tissue deposition of normally soluble proteins, or their fragments, as inso luble amyloid fibrils causes the usually fatal, acquired and hereditary sys temic amyloidoses and is associated with the pathology of Alzheimer's disea se, type 2 diabetes and the transmissible spongiform encephalopathies. Alth ough each type of amyloidosis is characterised by a specific amyloid fibril protein, the deposits share pathognomonic histochemical properties and the structural morphology of all amyloid fibrils is very similar. We have prev iously demonstrated that transthyretin amyloid fibrils contain four constit uent protofilaments packed in a square array. Here, we have used cross-corr elation techniques to average electron microscopy images of multiple cross- sections in order to reconstruct the sub-structure of ex vivo amyloid fibri ls composed of amyloid A protein, monoclonal immunoglobulin lambda light ch ain, Leu60Arg variant apolipoprotein Al, and Asp67His variant lysozyme, as well as synthetic fibrils derived from a ten-residue peptide corresponding to the A-strand of transthyretin. All the fibrils had an electron-lucent co re but the packing arrangement comprised five or six protofilaments rather than four. The structural similarity that defines amyloid fibres thus exist s principally at the level of beta-sheet folding of the polypeptides within the protofilament, while the different types vary in the supramolecular as sembly of their protofilaments. (C) 2000 Academic Press.