TY - JOUR T1 - Coronavirus hemagglutinin-esterase and spike proteins co-evolve for functional balance and optimal virion avidity JF - bioRxiv DO - 10.1101/2020.04.03.003699 SP - 2020.04.03.003699 AU - Yifei Lang AU - Wentao Li AU - Zeshi Li AU - Danielle Koerhuis AU - Arthur C.S. van den Burg AU - Erik Rozemuller AU - Berend-Jan Bosch AU - Frank J.M. van Kuppeveld AU - Geert-Jan P.H. Boons AU - Eric G. Huizinga AU - Hilde M. van der Schaar AU - Raoul J. de Groot Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/05/2020.04.03.003699.abstract N2 - Human coronaviruses OC43 and HKU1 are respiratory pathogen of zoonotic origin that have gained worldwide distribution. OC43 apparently emerged from a bovine coronavirus (BCoV) spill-over. 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 towards 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 selected for 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 co-evolve 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 (IAVs). Apparently, general principles fundamental to virion-sialoglycan interactions prompted convergent evolution of two important groups of human and animal pathogens. ER -