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

By R. Hulswit, Yifei Lang, M. Bakkers, Wentao Li, Zeshi Li, A. Schouten, Bram Ophorst, F. V. van Kuppeveld, G. Boons, B. Bosch and 2 more. 2019

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Significance Human coronaviruses OC43 and HKU1 are related, yet distinct respiratory pathogens, associated with common colds, but also with severe disease in the frail. Both viruses employ sialoglycan-based receptors with 9-O-acetylated sialic acid (9-O-Ac-Sia) as key component. Here, we identify the 9-O-Ac-Sia–specific receptor-binding site of OC43 S and demonstrate it to be conserved and functional in HKU1. The considerable difference in receptor-binding affinity between OC43 and HKU1 S, attributable to differences in local architecture and receptor-binding site accessibility, is suggestive of differences between OC43 and HKU1 in their adaptation to the human sialome. The data will enable studies into the evolution and pathobiology of OC43 and HKU1 and open new avenues toward prophylactic and therapeutic intervention. Human betacoronaviruses OC43 and HKU1 are endemic respiratory pathogens and, while related, originated from independent zoonotic introductions. OC43 is in fact a host-range variant of the species Betacoronavirus-1, and more closely related to bovine coronavirus (BCoV)—its presumptive ancestor—and porcine hemagglutinating encephalomyelitis virus (PHEV). The β1-coronaviruses (β1CoVs) and HKU1 employ glycan-based receptors carrying 9-O-acetylated sialic acid (9-O-Ac-Sia). Receptor binding is mediated by spike protein S, the main determinant of coronavirus host specificity. For BCoV, a crystal structure for the receptor-binding domain S1A is available and for HKU1 a cryoelectron microscopy structure of the complete S ectodomain. However, the location of the receptor-binding site (RBS), arguably the single-most important piece of information, is unknown. Here we solved the 3.0-Å crystal structure of PHEV S1A. We then took a comparative structural analysis approach to map the β1CoV S RBS, using the general design of 9-O-Ac-Sia-binding sites as blueprint, backed-up by automated ligand docking, structure-guided mutagenesis of OC43, BCoV, and PHEV S1A, and infectivity assays with BCoV-S–pseudotyped vesicular stomatitis viruses. The RBS is not exclusive to OC43 and related animal viruses, but is apparently conserved and functional also in HKU1 S1A. The binding affinity of the HKU1 S RBS toward short sialoglycans is significantly lower than that of OC43, which we attribute to differences in local architecture and accessibility, and which may be indicative for differences between the two viruses in receptor fine-specificity. Our findings challenge reports that would map the OC43 RBS elsewhere in S1A and that of HKU1 in domain S1B.

Subfields: Animal Science and Zoology, Genetics, Infectious Diseases

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Citations in the corpus

SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2 (2020, background): “acetylneuraminic acid (Hulswit et al., 2019; Tortorici et al., 2019), middle east respiratory syndrome virus (MERS) binds 5-N-acetyl-neuraminic acid (Park et al.”
Characteristics of and Public Health Responses to the Coronavirus Disease 2019 Outbreak in China (2020, background): “There are six kinds of coronaviruses known to infect humans, including 229E and NL63 of α genus [15,16], OC43, HKU1, Middle East respiratory syndrome-associated coronavirus (MERSr-CoV), and severe acute respiratory syndrome-associated coronavirus (SARSr-CoV) of β genus [16,17].”
Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein (2020, background): “Endemic human coronaviruses OC43 and HKU1 attach via their S domain A (S) to 5-Nacetyl-9-O-acetyl-sialosides found on glycoproteins and glycolipids at the host cell surface to enable entry into susceptible cells (Hulswit et al., 2019; Tortorici et al., 2019; Vlasak et al., 1988).”
The human coronavirus HCoV-229E S-protein structure and receptor binding (2019, background): “HCoV-229E and 43 HCoV-NL63 are closely related alphacoronaviruses that use different host proteins as receptors 44 (8, 9), while HCoV-OC43 and HCoV-HKU1 are betacoronaviruses that both use 9-O-acetylsialic 45 acids as receptor(10, 11).”
SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2 (2020, neutral): “N -acetyl-9- O -acetyl- neuraminic acid (Hulswit et al., 2019; Tortorici et al., 2019), middle east respiratory syndrome virus (MERS-CoV) binds to 5-”
Structural insights into coronavirus entry (2019, background): “residues were shown to be essential for S-mediated viral entry (Hulswit et al., 2019; Tortorici et al., 2019) and 9-O-Ac-Sia depletion from target cells resulted in severe decrease in virus infectivity (Krempl et al.”