1. Three-dimensional structure of the lithostathine protofibril, a protein involved in Alzheimer's disease
- Author
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Jean-Michel Verdier, Jean Thimonier, Vincent Peyrot, Emmanuelle Laurine, Jean-Paul Chauvin, Catherine Grégoire, Sergio Marco, Bernard Michel, Laure Duplan, Interaction entre Systèmes Protéiques et Différenciation dans la Cellule Tumorale (ISPDCT), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire des protéines complexes (EA3290), Université de Tours (UT), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Unité de Neurogériatrie, Assistance Publique - Hôpitaux de Marseille (APHM), Université de Tours, and Verdier, Jean-Michel
- Subjects
Models, Molecular ,Protein Conformation ,MESH: Amino Acid Sequence ,MESH: Calcium-Binding Proteins ,Crystallography, X-Ray ,Microscopy, Atomic Force ,Protein Structure, Secondary ,Protein filament ,0302 clinical medicine ,Protein structure ,Calcium-binding protein ,Lithostathine ,Image Processing, Computer-Assisted ,Peptide sequence ,MESH: Lithostathine ,Sequence Deletion ,MESH: Microscopy, Atomic Force ,0303 health sciences ,General Neuroscience ,MESH: Image Processing, Computer-Assisted ,3. Good health ,Biochemistry ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,MESH: Models, Molecular ,MESH: Molecular S ,Amyloid ,Macromolecular Substances ,Molecular Sequence Data ,Nerve Tissue Proteins ,MESH: Microscopy, Electron ,Biology ,Fibril ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Tetramer ,Alzheimer Disease ,Humans ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Amino Acid Sequence ,Molecular Biology ,030304 developmental biology ,MESH: Humans ,General Immunology and Microbiology ,Calcium-Binding Proteins ,MESH: Macromolecular Substances ,MESH: Crystallography, X-Ray ,Microscopy, Electron ,Biophysics ,030217 neurology & neurosurgery ,MESH: Alzheimer 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.
- Published
- 2001