Coronavirus hemagglutinin-esterase and spike proteins co-evolve 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 P.H. Boons; Eric G. Huizinga; Hilde M. van der Schaar; Raoul J. de Groot

The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.03.003699 doi: bioRxiv preprint Thr 83 Asn and Leu 89 Pro), but with propagation thus recovered, derivatives rapidly emerged with 381 increased HE lectin and esterase activity through a Ser 116 Phe mutation. Apparently, this created an 382 HE-S disbalance that in turn favored the selection of viruses with revertant mutations in S that raised 383 S RBS affinity again to wildtype (Thr 83 → Ile → Thr; Leu 89 → Pro → Leu) or near wildtype levels (Thr 83 → Ile 384 → Ser; Leu 89 → Pro→ Thr/Ser). Conjointly, our findings indicate that through an initial sharp reduction in 385 overall avidity, compensatory to loss of HE function, virus particles regained the capacity of eluding catalytic virion release. We posit that in addition to an optimal balance between receptor-binding and 395 receptor-destruction, the system strives towards optimal virion avidity (Fig. 4C) . 396 Under natural circumstances, the set-point of the S/HE balance would be tailored to conditions met The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.03.003699 doi: bioRxiv preprint The copyright holder for this preprint (which was not peer-reviewed) is the . The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.03.003699 doi: bioRxiv preprint 553 1 Percental occurrence of BCoV S1 A mutations and 2 their relative binding affinities as measured by 554 equilibrium endpoint solid phase binding assay with S1 A -Fc fusion proteins with that of parental BCoV 555 S1 A -Fc ('wildtype') set at 1.0. S1 A variants Thr 22 Ile and Asn 27 Tyr emerged only in experiment 2 (see sFig.