Identification of the Receptor-Binding Domain of the Spike Glycoprotein of Human Betacoronavirus HKU1

Qian, Zhaohui; Ou, Xiuyuan; Góes, Luiz Gustavo Bentim; Osborne, Christina; Castano, Anna; Holmes, Kathryn V.; Dominguez, Samuel R.

doi:10.1128/jvi.03737-14

Cited by 53 publications

(72 citation statements)

References 50 publications

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“…29). To gain structural and molecular insights into the receptor binding motif and neutralizing epitopes, we carried out a crystallographic study on the CTD of the HKU1 S protein.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of the receptor binding domain of the spike glycoprotein of human betacoronavirus HKU1

Guan

Qin

et al. 2017

Nat Commun

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Human coronavirus (CoV) HKU1 is a pathogen causing acute respiratory illnesses and so far little is known about its biology. HKU1 virus uses its S1 subunit C-terminal domain (CTD) and not the N-terminal domain like other lineage A β-CoVs to bind to its yet unknown human receptor. Here we present the crystal structure of HKU1 CTD at 1.9 Å resolution. The structure consists of three subdomains: core, insertion and subdomain-1 (SD-1). While the structure of the core and SD-1 subdomains of HKU1 are highly similar to those of other β-CoVs, the insertion subdomain adopts a novel fold, which is largely invisible in the cryo-EM structure of the HKU1 S trimer. We identify five residues in the insertion subdomain that are critical for binding of neutralizing antibodies and two residues essential for receptor binding. Our study contributes to a better understanding of entry, immunity and evolution of CoV S proteins.

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“…29). To gain structural and molecular insights into the receptor binding motif and neutralizing epitopes, we carried out a crystallographic study on the CTD of the HKU1 S protein.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of the receptor binding domain of the spike glycoprotein of human betacoronavirus HKU1

Guan

Qin

et al. 2017

Nat Commun

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“…A positively selected site was located in the CTD, a region that has unclear function in the HCoV-OC43 S protein, as no known protein receptor has been identified to date [61]. However, recent data from HKU1 suggest that, by analogy, a protein receptor for HCoV-OC43 may exist [62] (see below).…”

Section: Hcov-oc43mentioning

confidence: 99%

“…The structure of the S protein of HKU1 was recently solved; the glycan-binding site is located in the NTD and is conserved with bovine coronavirus (BCoV) S1 [63]. Nonetheless, antibodies against the CTD, but not those against the NTD, block HKU1 infection of human trachealbronchial epithelial cells, suggesting that the CTD is the major RBD, and that a protein receptor for HKU1 exists [62]. In analogy to HCoV-NL63, glycans may mediate only the initial attachment to the host cells.…”

Section: Hcov-hku1mentioning

confidence: 99%

Molecular Evolution of Human Coronavirus Genomes

Forni

Cagliani

Clerici

et al. 2017

Trends in Microbiology

686

777

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Human coronaviruses (HCoVs), including SARS-CoV and MERS-CoV, are zoonotic pathogens that originated in wild animals. HCoVs have large genomes that encode a fixed array of structural and nonstructural components, as well as a variety of accessory proteins that differ in number and sequence even among closely related CoVs. Thus, in addition to recombination and mutation, HCoV genomes evolve through gene gains and losses. In this review we summarize recent findings on the molecular evolution of HCoV genomes, with special attention to recombination and adaptive events that generated new viral species and contributed to host shifts and to HCoV emergence. VIDEO ABSTRACT.

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“…Based on the galectin-like fold of the S1 A domain and mutational analysis, the RBS was predicted (17). Although this model remains to be confirmed, it has been widely accepted by the field (27,28,(31)(32)(33). Surprisingly, HKU1 S was recently reported to bind to its receptor via a domain other than S1 A (31).…”

mentioning

confidence: 99%

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

Hulswit

Lang

Bakkers

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

383

395

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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-Oacetylated 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 S1 A is available and for HKU1 a cryoelectron microscopy structure of the complete S ectodomain. However, the location of the receptorbinding site (RBS), arguably the single-most important piece of information, is unknown. Here we solved the 3.0-Å crystal structure of PHEV S1 A . We then took a comparative structural analysis approach to map the β1CoV S RBS, using the general design of 9-O-Ac-Siabinding sites as blueprint, backed-up by automated ligand docking, structure-guided mutagenesis of OC43, BCoV, and PHEV S1 A , 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 S1 A . 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 finespecificity. Our findings challenge reports that would map the OC43 RBS elsewhere in S1 A and that of HKU1 in domain S1 B .coronavirus | spike | 9-O-acetylated sialic acid | OC43 | HKU1 C oronaviruses (CoVs; order Nidovirales, family Coronaviridae) are enveloped positive-strand RNA viruses of mammals and birds. So far, four coronaviruses of zoonotic origin are known to have successfully breached the species barrier to become true human pathogens (1-6). These viruses-NL63, 229E, HKU1, and OC43-are persistently maintained in the human population through continuous circulation. Remarkably, the latter two both belong to a single minor clade, "lineage A," in the genus Betacoronavirus. Although generally associated with common colds, HKU1 and OC43 may cause severe and sometimes fatal pulmonary infections in the frail (7, 8), and in rare instances, OC43 may cause lethal encephalitis (9). OC43 and HKU1 are distinct viruses that entered the human population independently to seemingly follow convergent evolutionary trajectories in their adaptation to the novel host (10). OC43 is in fact more related to coronaviruses of ruminants, horses, dogs, rabbits, and swine, with which it has been united in a single species, Betacoronavirus-1.Lineage A betacoronaviruses like HKU1 and OC43 differ from other CoVs in that their virions possess two types of surface projections, both of which are involved in attachment: large 20-nm peplomer...

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Identification of the Receptor-Binding Domain of the Spike Glycoprotein of Human Betacoronavirus HKU1

Cited by 53 publications

References 50 publications

Crystal structure of the receptor binding domain of the spike glycoprotein of human betacoronavirus HKU1

Crystal structure of the receptor binding domain of the spike glycoprotein of human betacoronavirus HKU1

Molecular Evolution of Human Coronavirus Genomes

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

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