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| Item Type: | Article |
|---|---|
| Title: | Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease |
| Creators Name: | Laurine, E., Gregoire, C., Faendrich, M., Engemann, S., Marchal, S., Thion, L., Mohr, M., Monsarrat, B., Michel, B., Dobson, C.M., Wanker, E.E., 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 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Volume: | 278 |
| Number: | 51 |
| 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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