NR AEWE
AU Gregoire,C.; Marco,S.; Thimonier,J.; Duplan,L.; Laurine,E.; Chauvin,J.P.; Michel,B.; Peyrot,V.; Verdier,J.M.
TI Three-dimensional structure of the lithostathine protofibril, a protein involved in Alzheimer's disease
QU EMBO Journal 2001 Jul 2; 20(13): 3313-21
PT journal article
AB Neurodegenerative diseases are characterized by the presence of filamentous aggregates of proteins. We previously established that lithostathine is a protein overexpressed in the pre-clinical stages of Alzheimer's disease. Furthermore, it is present in the pathognomonic lesions associated with Alzheimer's disease. After self-proteolysis, the N-terminally truncated form of lithostathine leads to the formation of fibrillar aggregates. Here we observed using atomic force microscopy that these aggregates consisted of a network of protofibrils, each of which had a twisted appearance. Electron microscopy and image analysis showed that this twisted protofibril has a quadruple helical structure. Three-dimensional X-ray structural data and the results of biochemical experiments showed that when forming a protofibril, lithostathine was first assembled via lateral hydrophobic interactions into a tetramer. Each tetramer then linked up with another tetramer as the result of longitudinal electrostatic interactions. All these results were used to build a structural model for the lithostathine protofibril called the quadruple-helical filament (QHF-litho). In conclusion, lithostathine strongly resembles the prion protein in its dramatic proteolysis and amyloid proteins in its ability to form fibrils.
MH Alzheimer Disease/*metabolism; Amino Acid Sequence; Calcium-Binding Proteins/*chemistry/*ultrastructure; Crystallography, X-Ray; Human; Image Processing, Computer-Assisted; Macromolecular Systems; Microscopy, Atomic Force; Microscopy, Electron; Models, Molecular; Molecular Sequence Data; Nerve Tissue Proteins/metabolism/ultrastructure; Protein Conformation; Protein Structure, Secondary; Sequence Deletion; Support, Non-U.S. Gov't
AD UMR CNRS 6032, Faculte de Pharmacie, Marseille, France.
SP englisch
PO England