Abstract
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.
Highlights
Human coronavirus (CoV) HKU1 is a pathogen causing acute respiratory illnesses and so far little is known about its biology
We recently reported that the C-terminal domain (CTD) of the HKU1 S protein contained the receptor-binding domain (RBD) and the epitopes for neutralizing antibodies mHKUS-2 and mHKUS-3
Because SD-1 is connected to both N-terminal galectin-like domain (NTD) and CTD and the Y320A mutation in mouse hepatitis virus (MHV) S protein destabilizes the association between S1 and S2, we propose that SD-1 may serve as a key motif to allow receptor-induced conformational changes in either the NTD or CTD to be transmitted to other parts of the S protein
Summary
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 b-CoVs to bind to its yet unknown human receptor. Most CoVs from lineage A b-CoVs, including mouse hepatitis virus (MHV), human CoV OC43 and bovine coronavirus (BCoV), use their NTDs to bind either receptor protein or sialic acid[17,28]. We recently found that the HKU1 virus, another lineage A b-CoV, uses its CTD, rather than its NTD, in the S protein to bind to its unknown receptor[29]. Compared to the SARS-CoV and MERS-CoV, there is a 76-amino acid insertion (amino acid 490–565, numbering from the S protein of genotype A HKU1 virus) in the CTD of the HKU1 S protein (Supplementary Fig. 1), whose function is unknown. Specific examples include complexes of the SARS-CoV CTD with human angiotensin converting enzyme 2 (hACE2)[25], NL63 CTD with hACE2 (ref. 30), MERS-CoV CTD with human dipeptidyl peptidase 4 (hDPP4)[26,27], HKU4 (lineage C b-CoV) CTD with hDPP4
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