13 / 2024-10-08 20:34:45

Unraveling dynamics of paramyxovirus-sialoglycan receptor interactions

Sialoglycan-binding enveloped viruses often also possess receptor-destroying activity to avoid being immobilized by non-functional decoy receptors. The balance between binding and cleavage is an important determinant of host tropism. Sialic acid (Sia)-binding paramyxoviruses contain a hemagglutinin-neuraminidase (HN) protein that possesses both Sia-binding and -cleavage activities. Here we used biolayer interferometry (BLI) to perform kinetic analyses of the dynamic receptor interactions of several animal and human paramyxoviruses. We show that these viruses display strikingly different sialoglycan receptor interaction dynamics, which result from differences in their receptor-binding and -cleavage activities but are difficult to predict from Michalis-Menten kinetics using a small molecule substrate. Our results furthermore indicate that paramyxoviruses display sialidase-driven virion motility, similar to a lawnmower molecular motor, on a receptor-coated surface until a threshold receptor density is reached at which virions start to dissociate. As studies of virus-glycan receptor interactions are complicated by the low affinity of the individual interactions and the requirement of high titer virus stocks we subsequently developed paramyxo-viromimic nanoparticles that multivalently present recombinant soluble HN tetramers. These viromimic nanoparticles displayed similar dynamics of particle-receptor interactions as virions. This platform allowed us to demonstrate an allosteric network between the catalytic site and the second Sia-binding site in HN of Newcastle disease virus, while it was also applicable to influenza A virus. We propose this novel viromimic platform to be applicable to study the dynamics of multivalent virus-receptor interactions crucial for host tropism, eliminating the need to culture these viruses.