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Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses

Jonathan Abraham1, Kevin D Corbett, Michael Farzan

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

Nature Structural & Molecular Biology
|March 9, 2010
PubMed

Insights

New World hemorrhagic fever viruses attach to cells using their GP1 protein and human transferrin receptor 1 (TfR1). Structural analysis reveals how these viruses adapt to infect humans, likely through fortuitous binding to human TfR1.

Area of Science:

  • Virology
  • Structural Biology
  • Molecular Interactions

Background:

  • New World hemorrhagic fever arenaviruses are zoonotic pathogens transmitted by rodents.
  • The GP1 subunit of the viral surface glycoprotein is crucial for cell attachment via transferrin receptor 1 (TfR1).

Purpose of the Study:

  • To elucidate the structural basis of Machupo virus GP1 binding to human TfR1.
  • To understand the molecular determinants of New World arenavirus host specificity and zoonotic transmission.

Main Methods:

  • X-ray crystallography to determine the structure of Machupo virus GP1 bound to human TfR1.
  • Sequence analysis of arenavirus GP1s and their corresponding host receptors.
  • Pseudovirus infectivity assays using cells with mutated TfR1.

Main Results:

  • Atomic-level details of the GP1-TfR1 interface were resolved.
  • Specific TfR1 residues critical for New World arenavirus host specificity were identified.
  • Contacts at the TfR1 apical domain tip were shown to dictate infectivity by certain arenaviruses.

Conclusions:

  • The study clarifies the molecular mechanisms underlying New World arenavirus entry into human cells.
  • Viral zoonotic transmission is influenced by GP1-TfR1 interactions and sequence variations.
  • Pathogenic New World arenaviruses may have acquired human TfR1 affinity incidentally during adaptation to rodent hosts.

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