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Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses

Nature Structural & Molecular Biology volume 17, pages 438444 (2010) | Download Citation

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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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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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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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.

Competing interests

The authors declare no competing financial interests.

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Correspondence to Stephen C Harrison.

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https://doi.org/10.1038/nsmb.1772

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