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Journal of Virology, October 2001, p. 9532-9537, Vol. 75, No. 19
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.19.9532-9537.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Venezuelan Equine Encephalomyelitis Virus Structure
and Its Divergence from Old World Alphaviruses
Angel
Paredes,1
Kathy
Alwell-Warda,2
Scott C.
Weaver,2
Wah
Chiu,1 and
Stanley J.
Watowich3,*
National Center for Macromolecular Imaging,
Verna and Marrs McLean Department of Biochemistry and Molecular
Biology, Baylor College of Medicine, Houston, Texas
77030,1 and Department of Pathology and
the Center for Tropical Diseases2 and
the Department of Human Biological Chemistry & Genetics and
Sealy Center for Structural Biology,3 University
of Texas Medical Branch, Galveston, Texas 77555
Received 9 April 2001/Accepted 22 June 2001
 |
ABSTRACT |
Although alphaviruses have been extensively studied as model
systems for the structural organization of enveloped viruses, no
structures exist for the phylogenetically distinct eastern equine
encephalomyelitis (EEE)-Venezuelan equine encephalomyelitis (VEE)
lineage of New World alphaviruses. Here we report the 25-Å structure of VEE virus, obtained from electron cryomicroscopy and image
reconstruction. The envelope spike glycoproteins of VEE virus have a
T=4 icosahedral arrangement, similar to that observed in Old World
Sindbis, Semliki Forest, and Ross River alphaviruses. However, VEE
virus has pronounced differences in its nucleocapsid structure relative
to nucleocapsid structures repeatedly observed in Old World alphaviruses.
| |
TEXT |
Alphaviruses (family
Togaviridae) can be partitioned into several major
phylogenetic lineages or serocomplexes. The eastern equine
encephalomyelitis (EEE) and Venezuelan equine encephalomyelitis (VEE)
lineages are sisters and are restricted to the New World, while the
Sindbis-like (with the exception of Aura), Semliki Forest (with the
exception of Mayaro and Una), Barmah Forest, Middelburg, and Ndumu
lineages occur in the Old World (2, 16, 17). Each lineage
is associated with a characteristic pathogenicity, with infections by
EEE-VEE lineage viruses a leading cause of viral encephalitis in humans
and horses in the Americas (6). The molecular determinants
responsible for this phylogenetically dependent pathogenicity are unknown.
Alphaviruses are small enveloped viruses (6, 12) that
package an ~11.5-kb, positive-sense, single-stranded RNA genome. The
viral genome encodes four nonstructural (nsP1, nsP2, nsP3, and nsP4)
and five structural (capsid, E1, E2, E3, and 6k) proteins. This
relatively simple protein composition has made alphaviruses model
systems ideal for studying enveloped virus assembly and structure
(3, 6, 9, 13). Electron cryomicroscopy and image
reconstruction of Sindbis, Semliki Forest, Ross River, and Aura viruses
show that the envelope glycoproteins are arranged on the outer surface
of the virus as 80 trimers in a T=4 icosahedral lattice (3, 5, 9,
10, 15, 18). The capsid proteins form a T=4 icosahedral
nucleocapsid and are arranged into distinct pentameric and hexameric
capsomeres on the exterior of the nucleocapsid (3, 9, 10).
The envelope and nucleocapsid structures are separated by a lipid
bilayer and likely interact through specific one-to-one interactions
between the capsid protein and the membrane-spanning tail of the E2
glycoprotein (7, 9, 14, 19). All currently known
alphavirus structures are from the Aura-Sindbis and Semliki Forest-Ross
River lineages (termed Old World lineage) and show very similar
envelope and nucleocapsid organization.
In this paper, we report the three-dimensional structure of VEE virus,
a New World virus from the EEE-VEE virus lineage, determined using
electron cryomicroscopy and image reconstruction. Comparison of the VEE
and Sindbis viruses showed that their envelope glycoproteins were
arranged similarly. However, the capsomere orientations within the VEE
and Sindbis virus nucleocapsids were different, implying that
alphavirus structures may differ according to their major phylogenetic lineages.
Purification, electron cryomicroscopy, and image reconstruction of
Sindbis and VEE viruses.
The structure of the Sindbis virus was
obtained from previous studies (9), with three-dimensional
image reconstructions performed using the cross-common-line method
(4). The Sindbis virus structure was reconstructed with
data truncated to 25 Å, with this resolution determined using
a value of 0.5 in the Fourier shell correlation coefficient method.
This structure was used in all comparisons with the VEE virus structure.
The TC-83 attenuated vaccine strain of VEE virus was a generous gift
from R. Shope and R. Tesh (Arbovirus Reference Center collection,
University of Texas Medical Branch). The TC-83 strain differs from its
virulent parent, Trinidad donkey VEE virus, by single-amino-acid
changes in the nsP4 and E1 proteins and 5-amino-acid changes in the E2
protein (8). Baby hamster kidney cells were grown to
confluency and were inoculated with virus at a multiplicity of
approximately 1.0. Infected cells were incubated at 37°C for ~2
days until cytopathic effects appeared; then the supernatant was pooled
and centrifuged for 10 min at 5,000 × g to remove
cellular debris. The virus was concentrated by precipitation with 7%
polyethylene glycol 8000 and 2.3% NaCl at 4°C for 8 to 16 h and
was gently resuspended in TN buffer (20 mM triethanolamine, pH 7.4, and
100 mM NaCl). Following centrifugation at 6,000 × g
for 30 min at 4°C, the resuspended pellet was purified by
centrifugation through a 20 to 70% continuous sucrose gradient for 60 min at 270,000 × g. Fractions containing the visible
virus band were pelleted through a 30% sucrose cushion for 120 min at
270,000 × g and were resuspended in TN buffer.
Purified VEE virus was applied to carbon-coated fenestrated grids,
flash cooled in a liquid ethane slush to preserve the sample
in
vitreous ice, and transferred into a JEOL 1200 electron cryomicroscope.
Virus images were recorded at 100 kV using flood beam imaging
and a
nominal magnification of ×30,000. To prevent specimen damage
from
electron irradiation, the illumination of the specimen with
the beam
was limited to five to seven electrons/Å
2 per
image. Two images per specimen area were recorded, with the
first image
being closer to 1.0-µm defocus and the second being
closer to
2.0-µm defocus. Reconstruction utilized hierarchical
wavelet
transformation and projection matching to determine initial
orientations as described previously (
11). Previously
determined
Sindbis virus reconstructions were used to generate the
initial
projections needed for the projection matching protocol. VEE
virus
reconstructions were used in subsequent iterative cycles of
orientation
refinement using the Fourier cross-common-line procedure,
which
was then used in the final image
reconstruction.
To ensure accurate comparisons of the VEE and Sindbis virus structures,
both structures were reconstructed at equivalent resolutions
(
1). The final VEE virus structure was reconstructed to 25
Å. Resolution was determined by the Fourier shell correlation
coefficient where a value of 0.5 was used to assign the resolution
limit.
Structure of VEE virus.
X-ray solution scattering data for VEE
virus and micrographs of tobacco mosaic virus were both used to
accurately determine the magnification of the electron cryomicroscope
and the pixel size of the digitized electron micrographs (data not
shown). Based on this calibration, the diameter of VEE virus was
calculated as 684 Å, in agreement with the diameter of
Sindbis virus (9). The VEE virus structure was composed of
80 envelope protein trimers on the surface of the virion. Each trimer
formed part of a series of overlapping pentameric and hexameric
capsomeres arranged on a T=4 icosahedral lattice (Fig.
1A). Similar arrangements of the envelope
glycoproteins were observed for Sindbis virus (Fig. 1B) and other
published alphavirus structures (3, 9, 10, 15, 18). The
envelope trimers had the characteristic counterclockwise twisted
hand typical of all alphaviruses and rose ~50 Å above the
envelope protein planar skirt (denoted by blue regions in Fig. 1). All
trimers had an outer diameter of ~139 Å, with their tips
separated from one another by ~107 Å.
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FIG. 1.
Structure of VEE and Sindbis viruses as determined by
image reconstructions of electron micrographs. (A) Isosurface view
along a threefold axis of the VEE virus reconstruction. Yellow
indicates the outer spike trimers, and blue indicates the skirt region
of the envelope. (B) Isosurface view along a threefold axis of the
Sindbis virus reconstruction. Yellow indicates the outer spike trimers,
and blue indicates the skirt region of the envelope. (C) Isosurface
representation of VEE virus nucleocapsid viewed along a
threefold-symmetry axis. (D) Isosurface representation of Sindbis virus
nucleocapsid viewed along a threefold-symmetry axis. (E) Cross-section
through VEE virus perpendicular to the threefold axis and in plane with
a vertical fivefold axis. The structural components of the virus are
color-coded: yellow indicates the trimers, blue indicates the skirt
region, red indicates the virus membrane, green indicates the
nucleocapsid, and white indicates the RNA genome. (F) Cross-section
through Sindbis virus perpendicular to the threefold axis and in plane
with a vertical fivefold axis. The structural components of the virus
are color-coded: yellow indicates the trimers, blue indicates the skirt
region, red indicates the virus membrane, green indicates the
nucleocapsid, and white indicates the RNA genome. Scale bar corresponds
to 100 Å.
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The radial distributions of the structural proteins were similar in
both VEE and Sindbis viruses (Fig.
1E and F). In both
structures, the
envelope skirt was ~50 Å thick and its outer
edge was
situated at a radius of 294 Å. The envelope skirt was
adjacent to the outer leaflet of the virus membrane. The
~40-Å
virus membrane occupied the region between a radius
of 201 and
240 Å and separated the nucleocapsid from the
envelope of the
virus.
The capsid proteins forming the surface of the VEE and Sindbis virus
nucleocapsids were arranged as both pentameric and hexameric
capsomeres
on a T=4 icosahedral lattice (Fig.
1C and D). The nucleocapsids
of both
VEE and Sindbis viruses were ~392 Å in diameter. The
capsid
protein making up the nucleocapsid structure measured ~60
Å
thick and extended inward to a radius of 136 Å. The inner
tier of the nucleocapsid, composed of the capsid N-terminal region
(CNR; residues 1 to ~115) complexed with viral RNA, adopted a
similar
shape in both the VEE and Sindbis viruses. Although this
region was
difficult to observe through rendering, radial density
plots examining
several VEE and Sindbis virus maps indicated that
this region extended
down to a radius of ~125 Å. As shown in
the cross-sections
normal to the threefold axis of the icosahedral
reconstructions, the
inner tier of the nucleocapsid had a distinct
polyhedral outline in the
VEE and Sindbis viruses (Fig.
1E and
F). The CNR complexed with bound
RNA likely adopted an extended
planar structure in the icosahedral
sides that bound the nucleocapsid
inner tier. The remainder of the
virus core is believed composed
of the RNA
genome.
Differences in nucleocapsids of VEE and Sindbis viruses.
The
envelope glycoprotein surfaces of VEE and Sindbis viruses overlapped
extensively when superimposed, demonstrating that their structures and
orientations were similar at the resolution of these reconstructions
(data not shown). In addition, the agreement in their surface
structures demonstrated that no systematic errors were preferentially
propagated in either of these reconstructions.
Unexpectedly, the nucleocapsid surfaces of VEE and Sindbis viruses did
not overlap when superimposed on one another (Fig.
2). Pronounced differences in the VEE and
Sindbis virus nucleocapsid
capsomere orientations and structure were
observed (Fig.
1C and
D). Reconstructions of VEE virus at different
resolutions and
from data collected on different electron
cryomicroscopes operating
at different accelerating voltages were
calculated (data not shown)
and were compared to all the published
nucleocapsid structures
before we concluded that the differences
between the Sindbis and
VEE virus nucleocapsid structures were
consistent, significant,
and real. Since TC-83 and wild-type VEE virus
capsid proteins
have identical primary structures, their tertiary and
quaternary
structures will likewise be identical. Thus, the wild-type
VEE
virus will likely have the same nucleocapsid capsomere arrangement
observed for the TC-83 VEE virus.
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FIG. 2.
Superposition of isosurfaces of nucleocapsids from VEE
(yellow) and Sindbis (blue) viruses showing the different orientations
of their pentameric and hexameric capsomeres. Arrows indicate the
positions of representative CCD proteins within the capsomeres.
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|
The pentameric and hexameric capsomeres that formed the VEE virus
nucleocapsid were rotated counterclockwise ~11 and ~4°,
respectively, relative to the corresponding Sindbis virus capsomeres.
Comparable rotational differences were observed when higher-resolution
reconstructions of the Sindbis virus structure were compared to
the VEE
virus structure. The triangular projections that comprise
the outer
ring structure of the nucleocapsid capsomeres (indicated
by arrows in
Fig.
2) are believed to correspond to the capsid
C-terminal domain
(CCD) (
3,
9). The organization of these
domains in VEE
virus was symmetrically directed towards one another,
giving the
nucleocapsid a mirrored, symmetrical appearance from
the tip of the
fivefold capsomere to the strict threefold axis
(Fig.
3A). As a result, the VEE virus CCDs
appeared organized
about threefold axes at all junctions of three
mutually adjacent
capsomeres (Fig.
1C and
3A). In contrast to the VEE
virus capsomere
arrangement, adjacent Sindbis virus capsomeres adopted
a gearlike
arrangement whereby the triangular projection of one
capsomere
was directed towards an indentation on an adjacent capsomere
(Fig.
1D and
3B). The relative positioning of the Sindbis virus CCDs
differed at the different capsomere junctions, with only
pseudothreefold
symmetry maintained at junctions between one pentameric
and two
hexameric capsomeres (Fig.
3B). Thus, regions of the capsid
protein
involved in intercapsomeric contacts will likely be different
for VEE and Sindbis viruses.
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FIG. 3.
Schematic representation of capsomere organization
within a triangular face of the nucleocapsid icosahedral structure. The
small triangular elements within each capsomere represent CCD
molecules. (A) Pentameric and hexameric capsomere organization within
the nucleocapsid of VEE virus. (B) Pentameric and hexameric capsomere
organization within the nucleocapsid of the Sindbis virus.
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|
To determine how symmetrical the strict threefold and quasithreefold
trimers were, sections normal to these trimers were isolated,
cross-correlation coefficients were calculated between each section
and
the same section rotated 120° about the normal axis of symmetry.
As
expected, the strict threefold positions demonstrated threefold
symmetry with correlation coefficients of ~0.9. In addition, both
viruses had correlation coefficients of ~0.9 at the quasithreefold
positions of the envelope trimers that extended outwards from
the
envelope skirt region. The correlation coefficient dropped
to ~0.65
at the quasithreefold positions occupied by the Sindbis
virus CCD,
while the correlation coefficient was >0.9 for the
corresponding
region of VEE virus. Comparison of these structures
showed that the
quasithreefold positions in the Sindbis virus
nucleocapsid were
disrupted by an inherent handedness or skew
of the CCD structure. In
contrast to Sindbis virus, the threefold
arrangement of VEE virus
capsid proteins closely mirrored the
organization of the trimeric
envelope proteins on the virus surface.
This arrangement implies a
one-to-one interaction between envelope
and capsid proteins and
suggests that capsid trimers may mediate
nucleocapsid assembly either
as nucleation structures or by cross-linking
capsomeres.
The capsomere triangular projections were more pronounced in VEE virus
than in the Sindbis virus (Fig.
2B). The electron density
connecting
these projections within the VEE virus capsomeres was
weaker than
within the Sindbis virus capsomeres. These observations
suggested that
capsid protein orientations and intermolecular
contacts may be
different in VEE and Sindbis viruses. Approximately
65% of the
residues proposed to form intermolecular CCD contacts
within Old World
alphavirus capsomeres (
3,
4,
9) were
found conserved in
VEE virus. Similar levels of sequence conservation
were calculated for
CCDs from VEE and Old World alphaviruses (Table
1), implying that putative intracapsomere
CCD contacts were not
perferentially conserved and thus may not be
necessary for capsomere
assembly.
Divergence of alphavirus structural proteins.
The Old World
Sindbis, Semliki Forest, and Ross River alphaviruses have homologous
structures. In contrast, the phylogenetically distinct New World VEE
virus has pronounced differences in its nucleocapsid structure relative
to nucleocapsid structures repeatedly observed in Old World
alphaviruses. This structural divergence likely arose from
lineage-dependent differences that evolved long ago in the component
protein and/or RNA structures. Sequence comparisons between alphavirus
structural proteins (Table 1) showed that the E1 glycoprotein and the
CCD were highly conserved and thus may adopt similar structures. In
contrast, the E2 glycoprotein and the CNR had limited sequence
conservation between alphaviruses and may adopt different structures.
The E2 glycoprotein of Ross River virus had sequence identity similar
to that of the E2 glycoprotein of VEE and Sindbis viruses, while the
CNR of Ross River virus was more closely related to Sindbis virus
than to VEE virus. Thus, the structure of the CNR may be lineage
dependent and ultimately responsible for the nucleocapsid structural
differences observed between phylogenetically distinct alphaviruses.
The secondary and tertiary structure of the viral RNA may also
contribute to the observed nucleocapsid structural differences.
Additional structural studies of New World alphaviruses will help
determine if the observed nucleocapsid capsomere orientations are
related to either the encephalitic potential of these viruses or to
their association with common reservoir vectors.
| |
ACKNOWLEDGMENTS |
This work was supported by grants from the John Sealy Memorial
Endowment Fund for Biomedical Research (2551-99, S. J. Watowich), the National Center for Macromolecular Imaging (P41R02250, W. Chiu), Robert Welch Foundation (Q-1242, W. Chiu), National Institute of
Allergy and Infectious Diseases (NIAID; T32-AI 07471, A. Paredes), and the Sealy Center for Structural Biology (University of Texas Medical Branch).
We thank V. Popov and M. Kunkel for assistance with electron microscopy
of negative-stained particles; R. Shope, B. V. V. Prasad, S. Ludtke, and J. Brink for helpful discussions; R. E. Johnston, D. Brown, and H. Heidner for access to the Sindbis virus structure; A. McGough for providing tobacco mosaic virus for magnification calibration; and M. Baker and W. Jiang for assistance in determining the cross-correlation coefficients of the strict and quasithreefold trimer positions.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Human Biological Chemistry & Genetics, University of Texas Medical
Branch, Galveston, TX 77555-0645. Phone: (409) 747-4749. Fax: (409)
747-4745. E-mail: watowich{at}bloch.utmb.edu.
| |
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Journal of Virology, October 2001, p. 9532-9537, Vol. 75, No. 19
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.19.9532-9537.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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