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

Author

Listed:
  • Szymon W. Manka

    (University College London)

  • Wenjuan Zhang

    (University College London)

  • Adam Wenborn

    (University College London)

  • Jemma Betts

    (University College London)

  • Susan Joiner

    (University College London)

  • Helen R. Saibil

    (University of London)

  • John Collinge

    (University College London)

  • Jonathan D. F. Wadsworth

    (University College London)

Abstract

Mammalian prions propagate as distinct strains and are composed of multichain assemblies of misfolded host-encoded prion protein (PrP). Here, we present a near-atomic resolution cryo-EM structure of PrP fibrils present in highly infectious prion rod preparations isolated from the brains of RML prion-infected mice. We found that prion rods comprise single-protofilament helical amyloid fibrils that coexist with twisted pairs of the same protofilaments. Each rung of the protofilament is formed by a single PrP monomer with the ordered core comprising PrP residues 94–225, which folds to create two asymmetric lobes with the N-linked glycans and the glycosylphosphatidylinositol anchor projecting from the C-terminal lobe. The overall architecture is comparable to that of recently reported PrP fibrils isolated from the brain of hamsters infected with the 263K prion strain. However, there are marked conformational variations that could result from differences in PrP sequence and/or represent distinguishing features of the distinct prion strains.

Suggested Citation

  • Szymon W. Manka & Wenjuan Zhang & Adam Wenborn & Jemma Betts & Susan Joiner & Helen R. Saibil & John Collinge & Jonathan D. F. Wadsworth, 2022. "2.7 Å cryo-EM structure of ex vivo RML prion fibrils," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30457-7
    DOI: 10.1038/s41467-022-30457-7
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    References listed on IDEAS

    as
    1. Benjamin Falcon & Wenjuan Zhang & Alexey G. Murzin & Garib Murshudov & Holly J. Garringer & Ruben Vidal & R. Anthony Crowther & Bernardino Ghetti & Sjors H. W. Scheres & Michel Goedert, 2018. "Structures of filaments from Pick’s disease reveal a novel tau protein fold," Nature, Nature, vol. 561(7721), pages 137-140, September.
    2. John Collinge, 2016. "Mammalian prions and their wider relevance in neurodegenerative diseases," Nature, Nature, vol. 539(7628), pages 217-226, November.
    3. Yang Shi & Wenjuan Zhang & Yang Yang & Alexey G. Murzin & Benjamin Falcon & Abhay Kotecha & Mike Beers & Airi Tarutani & Fuyuki Kametani & Holly J. Garringer & Ruben Vidal & Grace I. Hallinan & Tammar, 2021. "Structure-based classification of tauopathies," Nature, Nature, vol. 598(7880), pages 359-363, October.
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    Cited by:

    1. 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. B, 2022. "Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    2. Glenn C. Telling, 2022. "The shape of things to come: structural insights into how prion proteins encipher heritable information," Nature Communications, Nature, vol. 13(1), pages 1-3, December.
    3. Jing Tao & Yanping Zeng & Bin Dai & Yin Liu & Xiaohan Pan & Li-Qiang Wang & Jie Chen & Yu Zhou & Zuneng Lu & Liwei Xie & Yi Liang, 2023. "Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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