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Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease

Item Type:Article
Title:Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease
Creators Name:Laurine, E. and Gregoire, C. and Faendrich, M. and Engemann, S. and Marchal, S. and Thion, L. and Mohr, M. and Monsarrat, B. and Michel, B. and Dobson, C.M. and Wanker, E.E. and Erard, M. and Verdier, J.M.
Abstract:Autocatalytic cleavage of lithostathine leads to the formation of quadruple-helical fibrils (QHF-litho) that are present in Alzheimer's disease. Here we show that such fibrils also occur in Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases, where they form protease-K-resistant deposits and co-localize with amyloid plaques formed from prion protein. Lithostathine does not appear to change its native-like, globular structure during fibril formation. However, we obtained evidence that a cluster of six conserved tryptophans, positioned around a surface loop, could act as a mobile structural element that can be swapped between adjacent protein molecules, thereby enabling the formation of higher order fibril bundles. Despite their association with these clinical amyloid deposits, QHF-litho differ from typical amyloid fibrils in several ways, for example they produce a different infrared spectrum and cannot bind Congo Red, suggesting that they may not represent amyloid structures themselves. Instead, we suggest that lithostathine constitutes a novel component decorating disease-associated amyloid fibrils. Interestingly, [6,6′]bibenzothiazolyl-2,2′-diamine, an agent found previously to disrupt aggregates of huntingtin associated with Huntington's disease, can dissociate lithostathine bundles into individual protofilaments. Disrupting QHF-litho fibrils could therefore represent a novel therapeutic strategy to combat clinical amyloidoses.
Keywords:Amino Acid Sequence, Brain, Calcium-Binding Proteins, Congo Red, Creutzfeldt-Jakob Syndrome, Endopeptidase K, Fourier Transform Infrared Spectroscopy, Gerstmann-Straussler-Scheinker Disease, Immunohistochemistry, Lithostathine, Molecular Models, Nerve Tissue Proteins, Protein Conformation, Senile Plaques, Sequence Alignment, Spectrum Analysis
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:51770-51778
Date:1 January 2003
Official Publication:https://doi.org/10.1074/jbc.M306767200
PubMed:View item in PubMed

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