Prediction of amyloid fibril-forming proteins

In Alzheimer's disease and spongiform encephalopathies proteins transform f rom their native states into fibrils, We find that several amyloid-forming proteins harbor an a-helix in a polypeptide segment that should form a beta -strand according to secondary structure predictions. In 1324 nonredundant protein structures, 37 beta -strands with greater than or equal to7 residu es were predicted in segments where the experimentally determined structure s show helices, These discordances include the prion protein (helix 2, posi tions 179-191), the Alzheimer amyloid beta -peptide (alpha beta, positions 16-23), and lung surfactant protein C (SP-C, positions 12-27), In addition, human coagulation factor XIII (positions 258-266), triacylglycerol lipase from Candida antarctica (positions 256-266), and D-alanyl-D-alanine transpe ptidase from Streptomyces R61 (positions 92-106) contain a discordant helix , These proteins have not been reported to form fibrils hut in this study w ere found to form fibrils in buffered saline at pH 7.4. By replacing valine s in the discordant helical part of SP-C with leucines, an alpha -helix is found experimentally and by secondary structure predictions. This analogue does not form fibrils under conditions where SP-C forms abundant fibrils, L ikewise, when alpha beta residues 14-23 are removed or changed to a nondisc ordant sequence, fibrils are no longer formed. We propose that alpha -helix /beta -strand-discordant stretches are associated with amyloid fibril forma tion.