Structures and Activities of Prions and Prion Proteins

National Institute Of Allergy And Infectious Diseases

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Abstract

Within the extensive range of self-propagating pathologic protein aggregates of mammals, prions are the most clearly infectious (e.g. 109 lethal doses per mg). The structures of such lethal assemblies of PrP molecules have been poorly understood. We have now obtained the first near-atomic core structure of a brain-derived, fully infectious prion strain (263K scrapie). Our cryo-electron microscopy studies showed amyloid fibrils assembled with parallel in-register intermolecular beta sheets. Each monomer provides one rung of the ordered fibril core, with N-linked glycans and glycolipid anchors projecting outward. Thus, single monomers form the templating surface for incoming monomers at fibril ends, where prion growth occurs. Comparison to another prion strain (aRML scrapie) revealed major differences in fibril morphology, but like 263K, an asymmetric fibril cross-section without paired protofilaments. These findings provide structural insights into prion propagation, strains, species barriers, and membrane pathogenesis. This structure also helps frame considerations of factors influencing the relative transmissibility of other pathologic amyloids.