Fig. 6: Model for hetero-multivalent IAV binding.
a Avian IAV interactions with high-affinity (2-3Sia), low-affinity (2-6Sia) or mixed receptor surfaces. Arrow size indicates how kon and koff relatively compare. The initial, intermolecular and virus concentration dependent, monovalent interaction (KD = koff/kon ~ 1–20 mM) is characterized by a low binding rate constant kon (M−1 s−1) and high dissociation rate constant koff (s−1, half-life time of 0.5 to a few seconds)17,18,19,20,21. Additional interactions will lead to longer lasting virus-to-surface binding. The second, concentration-independent, interaction depends on the koff of the first interaction and a second kon2 that depends on the nature of, and accessibility to, a second glycan. A koff2 for virus dissociation is much lower than koff1 as it describes a bivalent interaction. This initiates a cascade of sequentially faster engagement of subsequent receptors. Thus, IAV binding rate primarily depends on an initial high-affinity interaction with a 2-3Sia receptor that determines the chance of forming additional interactions with high-affinity 2-3Sia receptors (left panel) or by hetero-multivalent interactions with low-affinity 2-6Sia receptors (middle panel). However, at a homogeneous 2-6Sia receptor surface (right panel), the KD for the initial interaction in combination with a 2nd kon for a 2-6Sia receptor will not support multivalent binding (note that reported KD values for low and high affinity receptors for IAV strains differ only ~1.5 to 3-fold19). b Hetero-multivalent binding via the HA receptor binding site (RBS, magenta), a vestigial esterase site (VES, grey) and a secondary Sia binding site (2SBS, orange) on NA. As an example potential interactions for a bi-antennary receptor carrying a 2-3Sia (purple) and 2-6Sia (light green) are shown: inter-trimeric (1) and intra-trimer binding (2) of the RBS; inter-trimeric (3) and intra-trimer (4) binding via the RBS and VES; HA-NA binding via RBS and 2SBS (5). c NA activity effects on heterogeneous receptor surfaces. NA catalytic site (white) activity depends on substrate structure, being higher on 2-3Sia (kcat1) than on 2-6Sia (kcat2). Catalytic activity can be affected by arrangement of receptors via the different binding sites, for instance by binding to 2SBS like in (6). NA activity drives virus motility by reducing receptor density (7). Created with BioRender.com.
