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Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses

Nature Structural & Molecular Biology volume 17, pages 438–444 (2010)Cite this article

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Abstract

New World hemorrhagic fever arenaviruses are rodent-borne agents that cause severe human disease. The GP1 subunit of the surface glycoprotein mediates cell attachment through transferrin receptor 1 (TfR1). We report the structure of Machupo virus (MACV) GP1 bound with human TfR1. Atomic details of the GP1-TfR1 interface clarify the importance of TfR1 residues implicated in New World arenavirus host specificity. Analysis of sequence variation among New World arenavirus GP1s and their host-species receptors, in light of the molecular structure, indicates determinants of viral zoonotic transmission. Infectivities of pseudoviruses in cells expressing mutated TfR1 confirm that contacts at the tip of the TfR1 apical domain determine the capacity of human TfR1 to mediate infection by particular New World arenaviruses. We propose that New World arenaviruses that are pathogenic to humans fortuitously acquired affinity for human TfR1 during adaptation to TfR1 of their natural hosts.

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Figure 1: Structure of the MACV GP1–human TfR1 complex.
Figure 2: MACV GP1.
Figure 3: Five interaction motifs in the MACV GP1-human TfR1 interface.
Figure 4: Conservation of the GP1-TfR1 interface.
Figure 5: Importance of the tip of the apical domain in determining the role of human TfR1 as a receptor for pathogenic New World arenaviruses.

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Acknowledgements

We thank M. Babyonyshev for help with protein production, S. Jenni for advice and instruction on methods of structure determination and the staff at NE-CAT (Advanced Photon Source, Argonne National Laboratory) for assistance with X-ray data collection. The work was supported by US National Institutes of Health grants CA13202 (to S.C.H.) and R01 AI074879 (to H.C.). S.C.H. is an investigator in the Howard Hughes Medical Institute. J.A. is a Howard Hughes Medical Institute Gilliam fellow. K.D.C. is a Helen Hay Whitney Foundation postdoctoral fellow.

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Authors and Affiliations

  1. Laboratory of Molecular Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Jonathan Abraham & Stephen C Harrison

  2. Department of Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Jonathan Abraham & Hyeryun Choe

  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Kevin D Corbett & Stephen C Harrison

  4. Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Center, Southborough, Massachusetts, USA

    Michael Farzan

  5. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA

    Stephen C Harrison

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  1. Jonathan Abraham
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  2. Kevin D Corbett
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  3. Michael Farzan
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  4. Hyeryun Choe
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  5. Stephen C Harrison
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Contributions

J.A. designed and performed the experiments, analyzed the data and wrote the paper; K.D.C. assisted with data collection, molecular replacement, re-interpretation of the unliganded TfR1 structures and edited the paper; M.F. and H.C. assisted with data analysis and interpretation and edited the paper; S.C.H. helped design experiments, advised on model building and interpretation and participated in writing and editing the paper.

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Correspondence to Stephen C Harrison.

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Abraham, J., Corbett, K., Farzan, M. et al. Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses. Nat Struct Mol Biol 17, 438–444 (2010). https://doi.org/10.1038/nsmb.1772

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