Abstract
Alphaviruses are enveloped RNA viruses that contain several human pathogens. Due to intrinsic heterogeneity of alphavirus particles, a high resolution structure of the virion is currently lacking. Here we provide a 3.5 Å cryo-EM structure of Sindbis virus, using block based reconstruction method that overcomes the heterogeneity problem. Our structural analysis identifies a number of conserved residues that play pivotal roles in the virus life cycle. We identify a hydrophobic pocket in the subdomain D of E2 protein that is stabilized by an unknown pocket factor near the viral membrane. Residues in the pocket are conserved in different alphaviruses. The pocket strengthens the interactions of the E1/E2 heterodimer and may facilitate virus assembly. Our study provides structural insights into alphaviruses that may inform the design of drugs and vaccines.
Highlights
Alphaviruses are enveloped RNA viruses that contain several human pathogens
In the block-based reconstruction method[23], three blocks with one block containing five trimers located near icosahedral five-fold symmetry axis, another block containing four trimers located near icosahedral three-fold symmetry axis and the third block containing 17 capsid protein (CP) were selected (Fig. 1a)
The loose interactions between trimers suggest that the efficiency of the assembly of the trimers into an icosahedral lattice by the trimer itself is low, which has been already observed in the assembly of alphavirus harboring CP mutants[6]
Summary
Alphaviruses are enveloped RNA viruses that contain several human pathogens. Due to intrinsic heterogeneity of alphavirus particles, a high resolution structure of the virion is currently lacking. The E2 protein is responsible for host cell receptor recognition It contains A, B, and C ectodomains as well as one subdomain D, which is composed of a loop and a helix located near the viral membrane connecting the Domain C with the transmembrane helix (TM)[2]. The stem region forms a loop in the virus[2] and packs against the homotrimer core, at least as observed in the trimeric and fusogenic crystal structure of E13. The acidic environment of the endosome causes an irreversible conformational rearrangement of E1 and E2 envelope glycoproteins in which E2 dissociates from E1 This is followed by E1 forming homotrimers exposing hydrophobic fusion loops. The formation of the homotrimers triggers the fusion of the viral membrane with the endosomal membrane, which results in the release of viral genome into the cytoplasm
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