Abstract
Lujo virus (LUJV) has emerged as a highly fatal human pathogen. Despite its membership among the Arenaviridae, LUJV does not classify with the known Old and New World groups of that viral family. Likewise, LUJV was recently found to use neuropilin-2 (NRP2) as a cellular receptor instead of the canonical receptors used by Old World and New World arenaviruses. The emergence of a deadly pathogen into human populations using an unprecedented entry route raises many questions regarding the mechanism of cell recognition. To provide the basis for combating LUJV in particular, and to increase our general understanding of the molecular changes that accompany an evolutionary switch to a new receptor for arenaviruses, we used X-ray crystallography to reveal how the GP1 receptor-binding domain of LUJV (LUJVGP1) recognizes NRP2. Structural data show that LUJVGP1 is more similar to Old World than to New World arenaviruses. Structural analysis supported by experimental validation further suggests that NRP2 recognition is metal-ion dependent and that the complete NRP2 binding site is formed in the context of the trimeric spike. Taken together, our data provide the mechanism for the cell attachment step of LUJV and present indispensable information for combating this phatogen.
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Acknowledgements
Diffraction experiments were performed in beamline ID23-2 at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. We are grateful to C. Zubieta at the ESRF for providing assistance in using beamline ID23-2. We thank R. Read from the University of Cambridge for his invaluable advice and contribution to the analysis of our crystallographic data. We thank D. Fass for providing critical comments and suggestions. Ron Diskin is an incumbent of the Tauro career development chair in biomedical research. Research in the Diskin lab is supported by a research grant from the Enoch Foundation, a research grant from the Abramson Family Center for Young Scientists, a research grant from Ms Rudolfine Steindling, by the Minerva Foundation with funding from the Federal German Ministry for Education and Research and by a grant from the Israel Science Foundation (grant No. 682/16).
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H.C.D. together with I.K. produced, purified and crystallized the LUJVGP1/NRP2 complex. H.C.D. and R.D. collected diffraction data. R.D. solved and analysed the structure. H.C.D. conducted structure/function studies. R.D. wrote the manuscript with the help of H.C.D.
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Supplementary Results, Supplementary Tables 1 and 2, Supplementary Figures 1–13, Supplementary References.
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Cohen-Dvashi, H., Kilimnik, I. & Diskin, R. Structural basis for receptor recognition by Lujo virus. Nat Microbiol 3, 1153–1160 (2018). https://doi.org/10.1038/s41564-018-0224-5
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DOI: https://doi.org/10.1038/s41564-018-0224-5
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