title: Three-dimensional structure of the lithostathine protofibril, a protein involved in Alzheimer's disease.
abstract: 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.
authors: UMR CNRS 6032, Faculté de Pharmacie, Marseille, France.
authors: C
authors: C
authors: Grégoire
authors: S
authors: S
authors: Marco
authors: J
authors: J
authors: Thimonier
authors: L
authors: L
authors: Duplan
authors: E
authors: E
authors: Laurine
authors: J P
authors: JP
authors: Chauvin
authors: B
authors: B
authors: Michel
authors: V
authors: V
authors: Peyrot
authors: J M
authors: JM
authors: Verdier
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D018360:Crystallography, X-Ray; D006801:Humans; D007091:Image Processing, Computer-Assisted; D051847:Lithostathine; D046911:Macromolecular Substances; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000648:ultrastructure; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017384:Sequence Deletion
chemical_list: D002135:Calcium-Binding Proteins; D051847:Lithostathine; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; C497617:REG1A protein, human