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2.7 Å cryo-EM structure of ex vivo RML prion fibrils

Szymon W Manka1, Wenjuan Zhang1, Adam Wenborn1

  • 1MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, 33 Cleveland Street, London, W1W 7FF, UK.

Nature Communications
|July 13, 2022
PubMed

Insights

Researchers reveal the near-atomic structure of prion protein (PrP) fibrils from RML prion-infected mice using cryo-EM. These amyloid fibrils show distinct protofilament arrangements, offering insights into prion strain diversity.

Area of Science:

  • Structural Biology
  • Neuroscience
  • Biochemistry

Background:

  • Mammalian prions are infectious agents composed of misfolded prion protein (PrP) that propagate as distinct strains.
  • Understanding the structural basis of prion strains is crucial for deciphering their pathogenesis.

Purpose of the Study:

  • To determine the near-atomic resolution structure of PrP fibrils from RML prion-infected mouse brains.
  • To elucidate the structural features that may underlie prion strain diversity.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to analyze highly infectious prion rod preparations.
  • Near-atomic resolution structural determination of PrP fibrils.

Main Results:

  • Prion rods contain single-protofilament helical amyloid fibrils and twisted pairs of these protofilaments.
  • The ordered core of each PrP monomer spans residues 94-225, forming two asymmetric lobes.
  • N-linked glycans and GPI anchor project from the C-terminal lobe.
  • The overall architecture is similar to 263K hamster prions but shows marked conformational variations.

Conclusions:

  • The determined structure provides detailed insights into the molecular architecture of RML prion fibrils.
  • Conformational variations in PrP fibrils may explain the existence of distinct prion strains.
  • This structural information is vital for understanding prion propagation and strain diversity.

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