Structural analysis of the evolutionary origins of influenza virus hemagglutinin and other viral lectins

Abstract

Influenza virus and other viruses use host cell surface sugars as receptors. Here we show that the sugar-binding domains in influenza virus hemagglutinin and other viral lectins share the same structural fold as human galectins (host lectins). Unlike the easily accessible sugar-binding sites in human galectins, the sugar-binding sites in viral lectins are hidden in cavities. We propose that these viral lectins originated from host lectins but have evolved to use hidden sugar-binding sites to evade host immune attacks.

Fig 1

Structural comparisons among viral lectins and human galectins. (A) Structural topologies of human galectins, rotavirus VP4, and adenovirus galectin domain. (B) Structural topology of coronavirus spike NTD. (C) Structural topologies of influenza virus HA, coronavirus HE, and torovirus HE. The β-strands are named according to the coronavirus spike NTD structure (4). A common subcore structure is in gray. (D to F) Crystal structures of human galectin-3 (D), coronavirus spike NTD (E), and influenza virus HA (F).

Fig 2

Sugar-binding sites in viral lectins and human galectins. The two β-sheets are in green and magenta. (A to E) Crystal structures of sugar-bound human galectin-3, rotavirus VP4, adenovirus galectin domain, influenza virus HA, and coronavirus spike NTD. Sugars are in blue. The asterisk indicates the sugar-binding site in coronavirus spike NTD that was identified by mutagenesis studies.