Pre-initiation and elongation structures of full-length La Crosse virus polymerase reveal functionally important conformational changes

Benoît Arragain, Grégory Effantin, Piotr Gerlach, Juan Reguera, Guy Schoehn, Stephen Cusack () and Hélène Malet ()
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Benoît Arragain: Institute for Structural Biology (IBS)
Grégory Effantin: Institute for Structural Biology (IBS)
Piotr Gerlach: European Molecular Biology Laboratory
Juan Reguera: European Molecular Biology Laboratory
Guy Schoehn: Institute for Structural Biology (IBS)
Stephen Cusack: European Molecular Biology Laboratory
Hélène Malet: Institute for Structural Biology (IBS)

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Bunyavirales is an order of segmented negative-strand RNA viruses comprising several life-threatening pathogens against which no effective treatment is currently available. Replication and transcription of the RNA genome constitute essential processes performed by the virally encoded multi-domain RNA-dependent RNA polymerase. Here, we describe the complete high-resolution cryo-EM structure of La Crosse virus polymerase. It reveals the presence of key protruding C-terminal domains, notably the cap-binding domain, which undergoes large movements related to its role in transcription initiation, and a zinc-binding domain that displays a fold not previously observed. We capture the polymerase structure at pre-initiation and elongation states, uncovering the coordinated movement of the priming loop, mid-thumb ring linker and lid domain required for the establishment of a ten-base-pair template-product RNA duplex before strand separation into respective exit tunnels. These structural details and the observed dynamics of key functional elements will be instrumental for structure-based development of polymerase inhibitors.

Date: 2020
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DOI: 10.1038/s41467-020-17349-4

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