Coronavirus hemagglutinin-esterase and spike proteins coevolve for functional balance and optimal virion avidity

Yifei Lang, Wentao Li, Zeshi Li, Danielle Koerhuis, Arthur C S van den Burg, Erik Rozemuller, Berend-Jan Bosch, Frank J M van Kuppeveld, Geert-Jan Boons, Eric G Huizinga, Hilde M van der Schaar, Raoul J de Groot

Research output: Contribution to journalArticleAcademicpeer-review


Human coronaviruses OC43 and HKU1 are respiratory pathogens of zoonotic origin that have gained worldwide distribution. OC43 apparently emerged from a bovine coronavirus (BCoV) spillover. All three viruses attach to 9-O-acetylated sialoglycans via spike protein S with hemagglutinin-esterase (HE) acting as a receptor-destroying enzyme. In BCoV, an HE lectin domain promotes esterase activity toward clustered substrates. OC43 and HKU1, however, lost HE lectin function as an adaptation to humans. Replaying OC43 evolution, we knocked out BCoV HE lectin function and performed forced evolution-population dynamics analysis. Loss of HE receptor binding selected for second-site mutations in S, decreasing S binding affinity by orders of magnitude. Irreversible HE mutations led to cooperativity in virus swarms with low-affinity S minority variants sustaining propagation of high-affinity majority phenotypes. Salvageable HE mutations induced successive second-site substitutions in both S and HE. Apparently, S and HE are functionally interdependent and coevolve to optimize the balance between attachment and release. This mechanism of glycan-based receptor usage, entailing a concerted, fine-tuned activity of two envelope protein species, is unique among CoVs, but reminiscent of that of influenza A viruses. Apparently, general principles fundamental to virion-sialoglycan interactions prompted convergent evolution of two important groups of human and animal pathogens.

Original languageEnglish
Pages (from-to)25759-25770
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number41
Publication statusPublished - 13 Oct 2020


  • coronavirus
  • hemagglutinin-esterase
  • spike
  • sialic acid
  • influenza virus


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