Molecular Cell
Volume 81, Issue 21, 4 November 2021, Pages 4540-4551.e6
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Short article
High-resolution structure and strain comparison of infectious mammalian prions

https://doi.org/10.1016/j.molcel.2021.08.011Get rights and content
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Highlights

  • Cryo-EM reveals parallel in-register structure for an infectious brain-derived prion

  • N-linked glycans and GPI anchor project outward from the fibril core

  • Comparison to another prion strain reveals distinct conformational templates

  • In silico modeling suggests a structural basis for a prion transmission barrier

Summary

Within the extensive range of self-propagating pathologic protein aggregates of mammals, prions are the most clearly infectious (e.g., ∼109 lethal doses per milligram). The structures of such lethal assemblies of PrP molecules have been poorly understood. Here we report a near-atomic core structure of a brain-derived, fully infectious prion (263K strain). Cryo-electron microscopy showed amyloid fibrils assembled with parallel in-register intermolecular β 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) 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.

Keywords

prion
cryo-electron microscopy
membrane
amyloid
glycan
glycophosphatidylinositol anchor
parallel in-register β sheet
infectious
strain
species barrier

Data and code availability

  • • The cryo-EM density map has been deposited in Electron Microscopy Data Bank and the 263K atomic coordinates have been deposited in the RCSB Protein Data Bank and are publicly available as of the date of publication. EMD: 23459; PDB: 7LNA. Source images for figures are available at Mendeley Data at https://doi.org/10.17632/97srt7m5cp.1.

  • • This paper does not report original code.

  • • Any additional information required to reanalyze the data reported in this work/paper is available from the Lead Contact upon request.

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