Abstract
The spike protein N-terminal domains (NTDs) of bovine coronavirus (BCoV) and mouse hepatitis coronavirus (MHV) recognize sugar and protein receptors, respectively, despite their significant sequence homology. We recently determined the crystal structure of MHV NTD complexed with its protein receptor murine carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which surprisingly revealed a human galectin (galactose-binding lectin) fold in MHV NTD. Here, we have determined at 1.55 Å resolution the crystal structure of BCoV NTD, which also has the human galectin fold. Using mutagenesis, we have located the sugar-binding site in BCoV NTD, which overlaps with the galactose-binding site in human galectins. Using a glycan array screen, we have identified 5-N-acetyl-9-O-acetylneuraminic acid as the preferred sugar substrate for BCoV NTD. Subtle structural differences between BCoV and MHV NTDs, primarily involving different conformations of receptor-binding loops, explain why BCoV NTD does not bind CEACAM1 and why MHV NTD does not bind sugar. These results suggest a successful viral evolution strategy in which coronaviruses stole a galectin from hosts, incorporated it into their spike protein, and evolved it into viral receptor-binding domains with altered sugar specificity in contemporary BCoV or novel protein specificity in contemporary MHV.
Highlights
Coronavirus spike protein N-terminal domains (NTDs) bind sugar or protein receptors
The crystal was a twin, application of the twinning operator allowed the structure to be determined by molecular replacement using mouse hepatitis coronavirus (MHV) NTD as the search model (Protein Data Bank code 3R4D) (Fig. 1, A and B)
Our results show that MHV NTD binds mCEACAM1a with high affinity and mCEACAM1b with low affinity, which is consistent with previous studies [31, 33, 34]
Summary
Coronavirus spike protein N-terminal domains (NTDs) bind sugar or protein receptors. Results: We determined crystal structure of bovine coronavirus NTD and located its sugar-binding site using mutagenesis. Significance: This study explores origin and evolution of coronavirus NTDs. The spike protein N-terminal domains (NTDs) of bovine coronavirus (BCoV) and mouse hepatitis coronavirus (MHV) recognize sugar and protein receptors, respectively, despite their significant sequence homology. We recently determined the crystal structure of MHV NTD complexed with its protein receptor murine carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which surprisingly revealed a human galectin (galactose-binding lectin) fold in MHV NTD. MHV NTD contains the same fold as human galectins (galactose-binding lectins) [22], it does not bind sugar [6] Instead, it binds mCEACAM1a through exclusive protein-proembryonic antigen-related cell adhesion molecule 1a; CEA, carcinoembryonic antigen; RBM, receptor-binding motif. We speculate on the evolutionary relationships among BCoV NTD, MHV NTD, and host galectins
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