Molecular organization and dynamics of the fusion protein Gc at the hantavirus surface

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Abstract

The hantavirus envelope glycoproteins Gn and Gc mediate virion assembly and cell entry, with Gc driving fusion of viral and endosomal membranes. Although the X-ray structures and overall arrangement of Gn and Gc on the hantavirus spikes are known, their detailed interactions are not. Here we show that the lateral contacts between spikes are mediated by the same 2-fold contacts observed in Gc crystals at neutral pH, allowing the engineering of disulfide bonds to cross-link spikes. Disrupting the observed dimer interface affects particle assembly and overall spike stability. We further show that the spikes display a temperature-dependent dynamic behavior at neutral pH, alternating between 'open' and 'closed' forms. We show that the open form exposes the Gc fusion loops but is off-pathway for productive Gc-induced membrane fusion and cell entry. These data also provide crucial new insights for the design of optimized Gn/Gc immunogens to elicit protective immune responses.

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All data generated or analysed during this study are represented in the manuscript. Numerical data and statistics summary data source is provided for all graphs (Figures 2C, 3A, 3B, 4A, 4B, 4C, 5C, 5E, 6A, 6B, 6C, 6D and 6E).

Article and author information

Author details

Eduardo A Bignon

Laboratorio de Virología Molecular, Fundación Ciencia and Vida, Santiago, Chile

Competing interests
Eduardo A Bignon, Is named inventor on a patent application describing disulfide bonds for hantavirus spike stabilization.(PCT/US19/22134).
Amelina Albornoz

Laboratorio de Virología Molecular, Fundación Ciencia and Vida, Santiago, Chile

Competing interests
No competing interests declared.
Pablo Guardado-Calvo

Structural Virology Unit, Virology Department, Institut Pasteur, CNRS UMR 3569, Paris, France

Competing interests
Pablo Guardado-Calvo, Is named inventor on a patent application describing disulfide bonds for hantavirus spike stabilization.(PCT/US19/22134).
Félix A Rey

Structural Virology Unit, Virology Department, Institut Pasteur, CNRS UMR 3569, Paris, France

For correspondence
felix.rey@pasteur.fr

Competing interests
Félix A Rey, Is named inventor on a patent application describing disulfide bonds for hantavirus spike stabilization.(PCT/US19/22134).
Nicole D Tischler

Laboratorio de Virología Molecular, Fundación Ciencia and Vida, Santiago, Chile

For correspondence
ntischler@cienciavida.org

Competing interests
Nicole D Tischler, Is named inventor on a patent application describing disulfide bonds for hantavirus spike stabilization.(PCT/US19/22134).

"This ORCID iD identifies the author of this article:" 0000-0002-4578-4780

Funding

Comisión Nacional de Investigación Científica y Tecnológica (Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT 1181799)

Nicole D Tischler

Comisión Nacional de Investigación Científica y Tecnológica (Programa de Apoyo a Centros con Financiamiento Basal 170004 to Fundación Ciencia and Vida)

Nicole D Tischler

Comisión Nacional de Investigación Científica y Tecnológica (FONDEQUIP EQM130092 for the improvement of BSL3 of Pontificia Universidad Católica de Chile)

Nicole D Tischler

Integrative Biology of Emerging Infectious Diseases Labex (French government´s (grant ANR-10-LABX-62-IBEID)

Félix A Rey

Labex IBEID (grant ANR-10-LABX-62-IBEID 4E AAP)

Pablo Guardado-Calvo
Félix A Rey

Infect-ERA IMI European network (Program)

Félix A Rey

Comisión Nacional de Investigación Científica y Tecnológica (Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT 3150695)

Amelina Albornoz

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.