Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9065-9. doi: 10.1073/pnas.0800502105. Epub 2008 Jun 11.
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 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.
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.
- Viral destruction of cell surface receptors. [Proc Natl Acad Sci U S A. 2008 (Figures!!)
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8807-8. doi: 10.1073/pnas.0804355105. Epub 2008 Jun 23.
Viral infection is initiated by the attachment of the virus to the
appropriate host cells. This process involves a series of dedicated
virion proteins that have evolved to specifically recognize one, or a
small number, of cell-surface molecules. Although a number of virus–host
attachment mechanisms involve direct protein–protein interactions,
carbohydrate molecules such as sialic acids (SAs) may also serve as
receptor-binding determinants. The binding of viral envelope
glycoproteins to carbohydrates on cell membranes plays a significant
role in infection by many viruses. In general, the glycoproteins of
several lipid-enveloped viruses, including orthmyxoviruses (influenza A,
B, and C), toroviruses, and coronaviruses, have three important
functions: to recognize the receptor on the cell surface, to mediate
viral fusion with the cell membrane, and to destroy the receptor.
In the
highly infectious influenza A and B viruses, the receptor-binding and
membrane-fusion activities of cell entry are carried out by the
glycoprotein hemagglutinin (HA) (Fig. 1a).
The receptor-destroying enzyme (RDE) activity important for virus
release is conducted by the glycoprotein/enzyme neuraminidase (NA).
In
influenza C virus, a single glycoprotein, the
hemagglutinin-esterase-fusion (HEF) protein, possesses all three
functions.
For a number of toroviruses and group 2a coronaviruses, the
glycoprotein hemagglutinin esterase (HE) has both receptor-destroying
and receptor-binding activities. However, the receptor-binding activity
of HE is considered accessory to that of the spike protein (S), a
receptor-binding and fusion protein (Fig. 1
b). Our understanding of the structure,
mechanism, and evolution of HA, HEF, NA, and S at the molecular level
has increased substantially over the past two decades because of the
availability of numerous x-ray structural models of these molecules in
the unliganded or receptor-bound complexes.
In contrast, a lack of
detailed structural studies on HE has hindered our understanding of its
function and evolution.
In this issue of PNAS, Zeng et al. (1)
report the x-ray structures of HE from bovine coronavirus (BCoV) in
both its unliganded and liganded forms. These structures and the
associated biochemical data reported provide us with new insight and
clues into the evolutionary relationships among corona-, toro-, and
influenza viruses.
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