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J Biol Chem. 2001 Apr 20;276(16):12945-50. Epub 2000 Dec 27.

Prediction of amyloid fibril-forming proteins.

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Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Medical Nobel Institute, Karolinska Institutet, S-171 77 Stockholm, Sweden.


In Alzheimer's disease and spongiform encephalopathies proteins transform from their native states into fibrils. We find that several amyloid-forming proteins harbor an alpha-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 > or =7 residues were predicted in segments where the experimentally determined structures show helices. These discordances include the prion protein (helix 2, positions 179-191), the Alzheimer amyloid beta-peptide (Abeta, 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 transpeptidase from Streptomyces R61 (positions 92-106) contain a discordant helix. These proteins have not been reported to form fibrils but in this study were found to form fibrils in buffered saline at pH 7.4. By replacing valines 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. Likewise, when Abeta residues 14-23 are removed or changed to a nondiscordant sequence, fibrils are no longer formed. We propose that alpha-helix/beta-strand-discordant stretches are associated with amyloid fibril formation.

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