Structures and Activities of Prions and Prion Proteins

National Institute Of Allergy And Infectious Diseases

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Abstract

Little is known about the structural basis of prion strains. The previous fiscal year we determined the first high-resolution structure of a bona fide brain-derived infectious mammalian prion, the hamster 263K strain. This year we have added a high (3.0 ) resolution cryo-electron microscopy-based structure of a second prion strain, namely the mouse anchorless RML scrapie strain which, like the 263K strain, is an amyloid fibril a parallel in-register intermolecular -sheet (PIRIBS)-based core. Several structural motifs are shared between these ex vivo prion strains, including an amino-proximal steric zipper and three -arches. However, detailed comparisons reveal variations in these shared structural topologies and other features. Unlike 263K and wildtype RML prions, the anchorless RML prions lack glycophosphatidylinositol anchors and are severely deficient in N-linked glycans. Nonetheless, the similarity of our anchorless RML structure to one reported for wildtype RML prion fibrils in a recent preprint indicates that these post-translational modifications do not substantially alter the amyloid core conformation. This work demonstrates both common and divergent structural features of prion strains at the near-atomic level.