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Conformational changes in Lassa virus L protein associated with promoter binding and RNA synthesis activity

Author

Listed:
  • Tomas Kouba

    (European Molecular Biology Laboratory)

  • Dominik Vogel

    (Bernhard Nocht Institute for Tropical Medicine)

  • Sigurdur R. Thorkelsson

    (University of Hamburg)

  • Emmanuelle R. J. Quemin

    (University of Hamburg)

  • Harry M. Williams

    (Bernhard Nocht Institute for Tropical Medicine)

  • Morlin Milewski

    (Bernhard Nocht Institute for Tropical Medicine)

  • Carola Busch

    (Bernhard Nocht Institute for Tropical Medicine)

  • Stephan Günther

    (Bernhard Nocht Institute for Tropical Medicine)

  • Kay Grünewald

    (University of Hamburg)

  • Maria Rosenthal

    (Bernhard Nocht Institute for Tropical Medicine)

  • Stephen Cusack

    (European Molecular Biology Laboratory)

Abstract

Lassa virus is endemic in West Africa and can cause severe hemorrhagic fever. The viral L protein transcribes and replicates the RNA genome via its RNA-dependent RNA polymerase activity. Here, we present nine cryo-EM structures of the L protein in the apo-, promoter-bound pre-initiation and active RNA synthesis states. We characterize distinct binding pockets for the conserved 3’ and 5’ promoter RNAs and show how full-promoter binding induces a distinct pre-initiation conformation. In the apo- and early elongation states, the endonuclease is inhibited by two distinct L protein peptides, whereas in the pre-initiation state it is uninhibited. In the early elongation state, a template-product duplex is bound in the active site cavity together with an incoming non-hydrolysable nucleotide and the full C-terminal region of the L protein, including the putative cap-binding domain, is well-ordered. These data advance our mechanistic understanding of how this flexible and multifunctional molecular machine is activated.

Suggested Citation

  • Tomas Kouba & Dominik Vogel & Sigurdur R. Thorkelsson & Emmanuelle R. J. Quemin & Harry M. Williams & Morlin Milewski & Carola Busch & Stephan Günther & Kay Grünewald & Maria Rosenthal & Stephen Cusac, 2021. "Conformational changes in Lassa virus L protein associated with promoter binding and RNA synthesis activity," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27305-5
    DOI: 10.1038/s41467-021-27305-5
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    References listed on IDEAS

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    1. Quentin Durieux Trouilleton & Dominique Housset & Paco Tarillon & Benoît Arragain & Hélène Malet, 2024. "Structural characterization of the oligomerization of full-length Hantaan virus polymerase into symmetric dimers and hexamers," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Quentin Durieux Trouilleton & Sergio Barata-García & Benoît Arragain & Juan Reguera & Hélène Malet, 2023. "Structures of active Hantaan virus polymerase uncover the mechanisms of Hantaviridae genome replication," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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