NR APJH
AU Laurine,E.; Gregoire,C.; Fändrich,M.; Engemann,S.; Marchal,S.; Thion,L.; Mohr,M.; Monsarrat,B.; Michel,B.; Dobson,C.M.; Wanker,E.; Erard,M.; Verdier,J.M.
TI Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease
QU The Journal of Biological Chemistry 2003 Dec 19; 278(51): 51770-8
PT journal article
AB 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.
MH Amino Acid Sequence; Brain/pathology; Calcium-Binding Proteins/analysis/*chemistry/*metabolism; Congo Red; Creutzfeldt-Jakob Syndrome/etiology/*metabolism; Endopeptidase K/*pharmacology; Gerstmann-Sträussler-Scheinker Disease/etiology/metabolism; Human; Immunohistochemistry; Models, Molecular; Protein Conformation; Senile Plaques/metabolism; Sequence Alignment; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Support, Non-U.S. Gov't
AD Ecole Pratique des Hautes Etudes, Montpellier 34095 cedex 05, France.
SP englisch
PO USA