Spike residue 403 affects binding of coronavirus spikes to human ACE2

Fabian Zech, Daniel Schniertshauer, Christoph Jung, Alexandra Herrmann, Arne Cordsmeier, Qinya Xie, Rayhane Nchioua, Caterina Prelli Bozzo, Meta Volcic, Lennart Koepke, Janis A. Müller, Jana Krüger, Sandra Heller, Steffen Stenger, Markus Hoffmann, Stefan Pöhlmann, Alexander Kleger, Timo Jacob, Karl-Klaus Conzelmann, Armin Ensser, Konstantin M. J. Sparrer and Frank Kirchhoff ()
Additional contact information
Fabian Zech: Institute of Molecular Virology, Ulm University Medical Center
Daniel Schniertshauer: Institute of Molecular Virology, Ulm University Medical Center
Christoph Jung: Institute of Electrochemistry, Ulm University
Alexandra Herrmann: Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg
Arne Cordsmeier: Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg
Qinya Xie: Institute of Molecular Virology, Ulm University Medical Center
Rayhane Nchioua: Institute of Molecular Virology, Ulm University Medical Center
Caterina Prelli Bozzo: Institute of Molecular Virology, Ulm University Medical Center
Meta Volcic: Institute of Molecular Virology, Ulm University Medical Center
Lennart Koepke: Institute of Molecular Virology, Ulm University Medical Center
Janis A. Müller: Institute of Molecular Virology, Ulm University Medical Center
Jana Krüger: Ulm University Medical Center
Sandra Heller: Ulm University Medical Center
Steffen Stenger: Institute of Medical Microbiology and Hygiene, Ulm University Medical Centre
Markus Hoffmann: Infection Biology Unit, German Primate Center—Leibniz Institute for Primate Research
Stefan Pöhlmann: Infection Biology Unit, German Primate Center—Leibniz Institute for Primate Research
Alexander Kleger: Ulm University Medical Center
Timo Jacob: Institute of Electrochemistry, Ulm University
Karl-Klaus Conzelmann: Max von Pettenkofer-Institute of Virology, Medical Faculty, and Gene Center, Ludwig-Maximilians-Universität München
Armin Ensser: Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg
Konstantin M. J. Sparrer: Institute of Molecular Virology, Ulm University Medical Center
Frank Kirchhoff: Institute of Molecular Virology, Ulm University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, the cause of the COVID-19 pandemic. However, this bat virus was most likely unable to directly infect humans since its Spike (S) protein does not interact efficiently with the human ACE2 receptor. Here, we show that a single T403R mutation increases binding of RaTG13 S to human ACE2 and allows VSV pseudoparticle infection of human lung cells and intestinal organoids. Conversely, mutation of R403T in the SARS-CoV-2 S reduces pseudoparticle infection and viral replication. The T403R RaTG13 S is neutralized by sera from individuals vaccinated against COVID-19 indicating that vaccination might protect against future zoonoses. Our data suggest that a positively charged amino acid at position 403 in the S protein is critical for efficient utilization of human ACE2 by S proteins of bat coronaviruses. This finding could help to better predict the zoonotic potential of animal coronaviruses.

Date: 2021
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DOI: 10.1038/s41467-021-27180-0

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