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Formation of amyloid fibrils by peptides derived from the bacterial cold shock protein CspB

  • MICHAEL GROß (a1), DEBORAH K. WILKINS (a1), MAUREEN C. PITKEATHLY (a1), EVONNE W. CHUNG (a1), CLAIRE HIGHAM (a2), ANNE CLARK (a2) and CHRISTOPHER M. DOBSON (a1)...

Abstract

Three peptides covering the sequence regions corresponding to the first two (CspB-1), the first three (CspB-2), and the last two (CspB-3) β-strands of CspB, the major cold shock protein of Bacillus subtilis, have been synthesized and analyzed for their conformations in solution and for their precipitation behavior. The peptides are nearly insoluble in water, but highly soluble in aqueous solutions containing 50% acetonitrile (pH 4.0). Upon shifts of the solvent condition toward lower or higher acetonitrile concentrations, the peptides all form fibrils resembling those observed in amyloid associated diseases. These fibrils have been identified and characterized by electron microscopy, binding of the dye congo red, and X-ray fiber diffraction. Characterization of the peptides in solution by circular dichroism and NMR spectroscopy shows that the formation of these fibrils does not require specific preformed secondary structure in the solution state species. While the majority of the soluble fraction of each peptide is monomeric and unstructured, different types of structures including α-helical, β-sheet, and random coil conformations are observed under conditions that eventually lead to fibril formation. We conclude that the absence of tertiary contacts under solution conditions where binding interactions between peptide units are still favorable is a crucial requirement for amyloid formation. Thus, fragmentation of a sequence, like partial chemical denaturation or mutation, can enhance the capacity of specific protein sequences to form such fibrils.

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Corresponding author

Reprint requests to: Christopher M. Dobson, Oxford Centre for Molecular Sciences, University of Oxford, New Chemistry Laboratory, Oxford OX1 3QT, United Kingdom; e-mail: chris.dobson@chemistry.oxford.ac.uk.

Keywords

Formation of amyloid fibrils by peptides derived from the bacterial cold shock protein CspB

  • MICHAEL GROß (a1), DEBORAH K. WILKINS (a1), MAUREEN C. PITKEATHLY (a1), EVONNE W. CHUNG (a1), CLAIRE HIGHAM (a2), ANNE CLARK (a2) and CHRISTOPHER M. DOBSON (a1)...

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