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Cap binding and immune evasion revealed by Lassa nucleoprotein structure

Abstract

Lassa virus, the causative agent of Lassa fever, causes thousands of deaths annually and is a biological threat agent, for which there is no vaccine and limited therapy. The nucleoprotein (NP) of Lassa virus has essential roles in viral RNA synthesis and immune suppression, the molecular mechanisms of which are poorly understood. Here we report the crystal structure of Lassa virus NP at 1.80 Å resolution, which reveals amino (N)- and carboxy (C)-terminal domains with structures unlike any of the reported viral NPs. The N domain folds into a novel structure with a deep cavity for binding the m7GpppN cap structure that is required for viral RNA transcription, whereas the C domain contains 3′–5′ exoribonuclease activity involved in suppressing interferon induction. To our knowledge this is the first X-ray crystal structure solved for an arenaviral NP, which reveals its unexpected functions and indicates unique mechanisms in cap binding and immune evasion. These findings provide great potential for vaccine and drug development.

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Figure 1: The crystal structure of LASV NP protein.
Figure 2: The C domain of LASV NP is a 3′–5′ exoribonuclease.
Figure 3: The exonuclease activity of NP is important for blocking the IFN induction.
Figure 4: The cap-binding residues and their roles in viral RNA transcription.

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Accession codes

Primary accessions

Protein Data Bank

Data deposits

Atomic coordinates and structure factors for the structures have been deposited in the Protein Data Bank under accession codes 3MWP for the native, 3MWT for themanganese complex, 3MX2 for the dTTP complex and 3MX5 for the UTP complex.

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Acknowledgements

C.D. wishes to thank J. Naismith for his continuing support, encouragement and advice; R. M. Elliott for providing the human β-globin containing plasmid phRL-CMV and his critical reading of the manuscript; H. Liu for discussions; and L. Major for the pLou3 plasmid. C.D. is a Wellcome trust career development fellow (083501/Z/07/Z). We thank the staff at IO2 and IO3 beam stations of Diamond light sources for their assistance with data collection. This work was supported in part by funds from the Southeast Regional Center of Excellence for Emerging Infections and Biodefense (5-U54-AI-057157-06), the pilot component of the U19 grant (5-U19-AI057266-07), and the Emory University Research Committee (URC) to Y.L. and H.L.; a seed grant from the Emory DDRDC (DK64399) and a research scholar grant from the American Cancer Society (RSG-06-162-01-GMC) to H.L.; NIH grant R01AI083409 to Y.L.; and NIH grant AI067704 to T. G. Parslow and Y.L. We thank K. Curtis and T. W. Geisbert for providing us with non-infectious genomic RNA samples of LASV, and J. Aronson for the PICV virus.

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X.Q., S.L., W.W., L.M.S., H.D. and G.D.W. performed experiments. C.D., Y.L. and H.L. conceived the idea for the study, performed some of the assays, participated in the analysis and interpretation of the data, and wrote the manuscript. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Hinh Ly, Yuying Liang or Changjiang Dong.

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Qi, X., Lan, S., Wang, W. et al. Cap binding and immune evasion revealed by Lassa nucleoprotein structure. Nature 468, 779–783 (2010). https://doi.org/10.1038/nature09605

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