Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains

• DOI: 10.1038/s41467-022-30458-6
• Publication Date: 2022-07-13T10:03:19Z
• Authors: Forrest Hoyt; Heidi G. Standke; Efrosini Artikis; Cindi L. Schwartz; Bryan Hansen; Kunpeng Li; Andrew G. Hughson; Matteo Manca; Olivia R. Thomas; Gregory J. Raymond; Brent Race; Gerald S. Baron; Byron Caughey; Allison Kraus
• Keywords: 0301 basic medicine; Amyloid; Sheep; Prions; Science; Q; Cryoelectron Microscopy; Brain; Article; Mice; 03 medical and health sciences; Animals; Scrapie

AbstractLittle is known about the structural basis of prion strains. Here we provide a high (3.0 Å) resolution cryo-electron microscopy-based structure of infectious brain-derived fibrils of the mouse anchorless RML scrapie strain which, like the recently determined hamster 263K strain, has a parallel in-register β-sheet-based core. Several structural motifs are shared between these ex vivo prion strains, including an amino-proximal steric zipper and three β-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 an accompanying paper 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.