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

Tomas Kouba, Dominik Vogel, Sigurdur R. Thorkelsson, Emmanuelle R. J. Quemin, Harry M. Williams, Morlin Milewski, Carola Busch, Stephan Günther, Kay Grünewald, Maria Rosenthal () and Stephen Cusack ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27305-5

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