This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Amyloids and filamentous viruses are filamentous biological assemblies, not suited to structural analysis by crystallography or NMR, but well suited to fiber diffraction. Amyloid fibers are formed when proteins change conformation to form insoluble filaments that can cause severe damage and even death. Amyloidoses include Alzheimer?s and Parkinson?s diseases and a variety of prion diseases including Creutzfeldt-Jakob disease and BSE (?mad cow disease?). Mammalian prions are infectious aggregates formed by the aberrantly folded protein PrP. Amyloids share a cross-beta structure, but structural details are not known. Fiber diffraction with electron microscopy, solid state NMR, and other approaches offers the best hope for elucidating structures of amyloids including prions. Structural studies are needed to answer fundamental protein folding questions, to understand amyloid formation, and for rational drug design. Synthetic prions derived from infectious recombinant protein have opened up new possibilities. Improved prion availability, improved methods of specimen preparation, and intense, high quality synchrotron radiation offer unprecedented opportunities to obtain amyloid diffraction data. Filamentous plant viruses are of enormous importance to agriculture, biotechnology and food security, but little is known about their molecular structures. Our structures from synchrotron diffraction data with cryo-electron microscopy are the only published structure determinations for these important pathogens. We use very small quantities of material to make dried fibers under controlled conditions. Fiber diffraction data will be obtained from brain-derived mammalian prions, from prion strains derived from infectious recombinant PrP, from the fungal prion HET-s, from the Alzheimer?s amyloid alpha/beta and other amyloids, and from filamentous plant viruses. The data will be used to evaluate and improve competing models for amyloid structure, and to determine filamentous virus structures.
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