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Support Address: support@nsc.liu.se |
Structure of Abeta protofibrils and spider silk fibers
AbstractAlzheimer’s disease (AD) is thought to be a result of neuronal damage caused by toxic aggregated forms of the amyloid-beta peptide (Abeta) in the brain. However, research on the molecular biology of soluble Abeta aggregates and their role in AD has been complicated by the inherent instability of these aggregates under test tube conditions. We have engineered a stable form of toxic aggregates without otherwise perturbing their structure and biological properties and this has opened the field for traditional structural and molecular biology research. However, the aggregates are too heterogeneous in size to form single crystals for X-ray diffraction and we therefore aim to determine the three-dimensional structure of toxic Abeta aggregates using a novel combination of experimental techniques. The research will potentially add significant insight into the underlying molecular mechanisms of AD and open for drug discovery and development of new therapeutic approaches. The structure of soluble Abeta aggregates is also of interest to biology in general as amyloid is a generic form of protein, but the mechanisms of amyloid formation are not yet fully understood. During the last year we have build a first model of Abeta protofibrils based on a unique set of experimental data from solid-state nuclear magnetic resonance (ssNMR) spectroscopy. We are now collecting additional structural data using peptide material with selective isotopic labeling to further refine our model. We also plan to include data from X-ray powder diffraction and small-angle X-ray scattering that contain information about aggregate size and morphology. Structural models of are being calculated using the Xplor and Rosetta software for molecular modeling. We are also applying the same methodology to investigate the structure of the protein fibers in spider silk. Spider silk is a natural high-performance polymer with excellent mechanical properties as well as high biocompatible and biodegradable. We are collaborating with the research group of My Hedhammar (SLU) that has developed a method to produce recombinant spider silk, which gives us the opportunity to produce isotopically labeled material for solid-state NMR studies. The project is expected to give new insights about the molecular architecture of spider silk fibers and an improved general understanding of the chemical principles of high-performance protein biomaterials. |
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