High-Resolution Structure of the N-Terminal Endonuclease Domain of the Lassa Virus L Polymerase in Complex with Magnesium Ions

Wallat, Gregor D., Huang, Qinfeng, Wang, Wenjian, Dong, Haohao, Ly, Hinh, Liang, Yuying and Dong, Changjiang (2014) High-Resolution Structure of the N-Terminal Endonuclease Domain of the Lassa Virus L Polymerase in Complex with Magnesium Ions. PLoS One, 9 (2). ISSN 1932-6203

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Abstract

Lassa virus (LASV) causes deadly hemorrhagic fever disease for which there are no vaccines and limited treatments. LASV-encoded L polymerase is required for viral RNA replication and transcription. The functional domains of L–a large protein of 2218 amino acid residues–are largely undefined, except for the centrally located RNA-dependent RNA polymerase (RdRP) motif. Recent structural and functional analyses of the N-terminal region of the L protein from lymphocytic choriomeningitis virus (LCMV), which is in the same Arenaviridae family as LASV, have identified an endonuclease domain that presumably cleaves the cap structures of host mRNAs in order to initiate viral transcription. Here we present a high-resolution crystal structure of the N-terminal 173-aa region of the LASV L protein (LASV L173) in complex with magnesium ions at 1.72 Å. The structure is highly homologous to other known viral endonucleases of arena- (LCMV NL1), orthomyxo- (influenza virus PA), and bunyaviruses (La Crosse virus NL1). Although the catalytic residues (D89, E102 and K122) are highly conserved among the known viral endonucleases, LASV L endonuclease structure shows some notable differences. Our data collected from in vitro endonuclease assays and a reporter-based LASV minigenome transcriptional assay in mammalian cells confirm structural prediction of LASV L173 as an active endonuclease. The high-resolution structure of the LASV L endonuclease domain in complex with magnesium ions should aid the development of antivirals against lethal Lassa hemorrhagic fever.

Item Type: Article
Additional Information: Copyright: © 2014 Wallat et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported in parts by the Wellcome trust fund (WT08351) and MRC (Medical Research Council) (G1100110/1) to CJD; NIH grants R01AI083409 to Y.L., and R56AI091805 and R01AI093580 to H.L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 13 May 2014 13:02
Last Modified: 21 Apr 2020 22:54
URI: https://ueaeprints.uea.ac.uk/id/eprint/47808
DOI: 10.1371/journal.pone.0087577

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