Structure of the infectious salmon anemia virus receptor complex illustrates a unique binding strategy for attachment

Abstract

Orthomyxoviruses are an important family of RNA viruses, which include the various influenza viruses. Despite global efforts to eradicate orthomyxoviral pathogens, these infections remain pervasive. One such orthomyxovirus, infectious salmon anemia virus (ISAV), spreads easily throughout farmed and wild salmonids, constituting a significant economic burden. ISAV entry requires the interplay of the virion-attached hemagglutinin-esterase and fusion glycoproteins. Preventing infections will rely on improved understanding of ISAV entry. Here, we present the crystal structures of ISAV hemagglutinin-esterase unbound and complexed with receptor. Several distinctive features observed in ISAV HE are not seen in any other viral glycoprotein. The structures reveal a unique mode of receptor binding that is dependent on the oligomeric assembly of hemagglutinin-esterase. Importantly, ISAV hemagglutininesterase receptor engagement does not initiate conformational rearrangements, suggesting a distinct viral entry mechanism. This work improves our understanding of ISAV pathogenesis and expands our knowledge on the overall diversity of viral glycoprotein-mediated entry mechanisms. Finally, it provides an atomic-resolution model of the primary neutralizing antigen critical for vaccine development.orthomyxovirus | viral fusion | viral attachment | hemagglutinin | infectious salmon anemia virus

Human coronaviruses OC43 and HKU1 bind to 9- O -acetylated sialic acids via a conserved receptor-binding site in spike protein domain A

“…From the combined results, we conclude that the actual RBS is located elsewhere. In further support, the RBS proposed by Peng et al (17)-henceforth referred to as "site A"-does not conform to the typical anatomy of O-Ac-Sia binding sites (18)(19)(20)(21)(22)(23)(24).…”

“…1C, but with data points representing mean averages of independent duplicate experiments. (C) Residual binding of PHEV and OC43 S1 A -Fc mutants with Ala substitutions of site A residues as detected by HAA, performed as in provide a wealth of structural data on how proteins recognize O-Ac-Sias (18)(19)(20)(21)(22)(23)(24). The O-acetyl Sia binding sites as they occur in HE lectin domains and esterase catalytic sites-despite major differences in structure and composition-conform to a common design in which ligand/substrate recognition is essentially based on shape complementarity and hydrophobic interactions, supported by protein-sugar hydrogen bonding involving characteristic Sia functions, such as the glycerol side chain, the 5-N-acyl moiety and, very often, the carboxylate.…”

“…Crystal structure analysis of orthomyxo-, toro-, and coronavirus HEs complexed to receptor/substrate analogs identified 9-O-Ac-Sia binding sites, yielding exquisite insight into the architecture of these sites and into the general principles of ligand/substrate recognition at the atomic level (18)(19)(20)(21)(22)(23)(24). Recently, cryoelectron microscopy (cryo-EM) structures were reported for several S proteins, including that of HKU1 (25)(26)(27)(28)(29).…”

Tilapia Lake Virus Does Not Hemagglutinate Avian and Piscine Erythrocytes and NH4Cl Does Not Inhibit Viral Replication In Vitro

“…This HE is unique when compared with the HA or hemagglutinin-esterase-fusion (HEF) proteins of other orthomyxoviruses, where the sequence identity is very low (<10%). The ISAV HE sequences shares sequence similarity with non-orthomyxoviruses, such as toroviruses and coronaviruses, by <25% [51][52][53]. It is this high specificity of the ISAV HE protein for Neu4,5Ac 2 glycans which make it different from other orthomyxoviruses, and may be what accounts for ISAV having lower tropism and mostly binding to fish RBCs, unlike other orthomyxoviruses which bind a wide range of RBCs from different avian, mammalian, and piscine species.…”

Interaction of the Amino-Terminal Domain of the ISAV Fusion Protein with a Cognate Cell Receptor

“…The ISAV envelope contains two major glycoproteins that mediate binding, membrane fusion, and receptor destruction. One of them is a hemagglutinin esterase (HE) which interacts with sialic acids on the susceptible cell surface via the hemagglutinin domain, promoting viral attachment; on the other hand, the esterase acts as a receptor-destroying enzyme (RDE), allowing the release of new viral particles in the context of a productive infection [10,11]. The second ISAV envelope protein is known as fusion protein (F) and mediates the fusion process of the viral and cellular membranes.…”