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. 2014 Jan;88(1):477-82.
doi: 10.1128/JVI.02641-13. Epub 2013 Oct 23.

Near-atomic Resolution Cryo-Electron Microscopic Structure of Dengue Serotype 4 Virus

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Free PMC article

Near-atomic Resolution Cryo-Electron Microscopic Structure of Dengue Serotype 4 Virus

Victor A Kostyuchenko et al. J Virol. .
Free PMC article

Abstract

Dengue virus (DENV), a mosquito-borne virus, is responsible for millions of cases of infections worldwide. There are four DENV serotypes (DENV1 to -4). After a primary DENV infection, the antibodies elicited confer lifetime protection against that DENV serotype. However, in a secondary infection with another serotype, the preexisting antibodies may cause antibody-dependent enhancement (ADE) of infection of macrophage cells, leading to the development of the more severe form of disease, dengue hemorrhagic fever. Thus, a safe vaccine should stimulate protection against all dengue serotypes simultaneously. To facilitate the development of a vaccine, good knowledge of different DENV serotype structures is crucial. Structures of DENV1 and DENV2 had been solved previously. Here we present a near-atomic resolution cryo-electron microscopy (cryo-EM) structure of mature DENV4. Comparison of the DENV4 structure with similar-resolution cryo-EM structures of DENV1 and DENV2 showed differences in surface charge distribution, which may explain their differences in binding to cellular receptors, such as heparin. Also, observed variations in amino acid residues involved in interactions between envelope and membrane proteins on the virus surface correlate with their ability to undergo structural changes at higher temperatures.

Figures

FIG 1
FIG 1
Cryo-EM structure of DENV4 solved to 4.1-Å resolution. (A) Surface of the DENV4 cryo-EM map. The black triangle shows the icosahedral asymmetric unit. Scale bar, 100 Å. (B) A quarter of a slice through the center, showing radial density distribution. The map is colored radially in panels A and B: up to 160 Å, yellow; 161 Å to 220 Å, green; 221 Å to 230 Å, blue; from 230 Å, magenta. (C) A view of the herringbone arrangement of the E proteins. The three individual E proteins in each asymmetric unit are colored in red, green, and blue. The E proteins in the raft in the center, which consist of two asymmetric units, are in brighter colors. (D and E) Views of the electron density map fitted with structures of the helical E stem region (D), showing densities corresponding to bulky side chains, and β-sheets (E), showing that the densities of β-strands are well separated. (F) A plot of Fourier shell correlation.
FIG 2
FIG 2
Structure of the envelope and M proteins on DENV4. (A) Structural organization of the E and M protein heterodimer. Following are the colors of the E protein domains: DI, red; DII, yellow (with the fusion loop in orange); DIII, blue; stem and transmembrane regions, green. The M protein is colored magenta. (B) Superposition of the three individual E proteins in an asymmetric unit. The transmembrane regions are removed for clarity. The most variable parts of the E protein are the loops involved in intradimeric contacts (marked “d”), interraft contacts (marked “r”), and icosahedral 3- and 5-vertex formation (marked “i”).
FIG 3
FIG 3
Comparing DENV4 with DENV2 and DENV1. (A) Superposition of the E protein structures from the three serotypes: DENV1 (red), DENV2 (green), and DENV4 (blue). There is very little structural variation, with an RMSD of less than 2 Å. (B) Surface charge distribution on a raft for DENV4 (left), DENV1 (center), and DENV2 (right). Red indicates negative charge; blue indicates positive charge. Despite high protein sequence similarity (more than 60% identity between DENV4 and DENV1 or DENV2), the charge distributions are different.
FIG 4
FIG 4
Abilities of the different DENV serotypes to undergo structural changes at elevated temperatures. Cryo-EM images of DENV4 strain SG/06K2270DK1/2005 (A), DENV1 strain PVP159 (B), and DENV2 strain NGC (C) after incubation at 37°C for 30 min are shown. The sizes of the DENV1 and DENV4 particles remained the same, and their surfaces appeared to be smooth, whereas DENV2 had expanded particles with a rough appearance. (D) DENV4 incubated at 40°C for 30 min. DENV4 particles aggregated together; however, the surfaces are not as bumpy as those of DENV2 at 37°C.

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