Structure of Coronavirus Hemagglutinin-Esterase Offers Insight into Corona and Influenza Virus Evolution

The hemagglutinin-esterases (HEs) are a family of viral envelope glycoproteins that mediate reversible attachment to O-acetylated sialic acids by acting both as lectins and as receptor-destroying enzymes (RDEs). Related HEs occur in influenza C, toro-, and coronaviruses, apparently as a result of re...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-07, Vol.105 (26), p.9065-9069
Main Authors: Zeng, Qinghong, Langereis, Martijn A., van Vliet, Arno L. W., Huizinga, Eric G., de Groot, Raoul J.
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Biological Evolution
Biological Sciences
Cattle
Cell Line
Conserved Sequence
Coronavirus
Coronavirus - enzymology
Coronavirus - genetics
Crystal structure
Crystallography, X-Ray
Crystals
Dimers
Evolution
Genes
Glycoproteins
Hemagglutinins, Viral - chemistry
Hemagglutinins, Viral - isolation & purification
Humans
Influenza
Influenza virus
Influenzavirus C
Ligands
Models, Molecular
Orthomyxoviridae
Orthomyxoviridae - genetics
Protein Structure, Secondary
Protein Structure, Tertiary
Proteins
Receptors
Receptors, Virus - metabolism
Recombinant Fusion Proteins - chemistry
Viral Fusion Proteins - chemistry
Viral Fusion Proteins - isolation & purification
Viruses
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Summary:The hemagglutinin-esterases (HEs) are a family of viral envelope glycoproteins that mediate reversible attachment to O-acetylated sialic acids by acting both as lectins and as receptor-destroying enzymes (RDEs). Related HEs occur in influenza C, toro-, and coronaviruses, apparently as a result of relatively recent lateral gene transfer events. Here, we report the crystal structure of a coronavirus (CoV) HE in complex with its receptor. We show that CoV HE arose from an influenza C-like HE fusion protein (HEF). In the process, HE was transformed from a trimer into a dimer, whereas remnants of the fusion domain were adapted to establish novel monomer-monomer contacts. Whereas the structural design of the RDE-acetylesterase domain remained unaltered, the HE receptor-binding domain underwent remodeling to such extent that the ligand is now bound in opposite orientation. This is surprising, because the architecture of the HEF site was preserved in influenza A HA over a much larger evolutionary distance, a switch in receptor specificity and extensive antigenic variation notwithstanding. Apparently, HA and HEF are under more stringent selective constraints than HE, limiting their exploration of alternative binding-site topologies. We attribute the plasticity of the CoV HE receptor-binding site to evolutionary flexibility conferred by functional redundancy between HE and its companion spike protein S. Our findings offer unique insights into the structural and functional consequences of independent protein evolution after interviral gene exchange and open potential avenues to broad-spectrum antiviral drug design.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0800502105