Zika Virus Structure, Maturation, and Receptors

Abstract

The emergence of Zika virus (ZIKV) as a major public health threat has focused research on understanding virus biology and developing a suite of strategies for disease intervention. Recent advances in cryoelectron microscopy have accelerated structure-function studies of flaviviruses and of ZIKV in particular. Structures of the mature and immature ZIKV have demonstrated its similarity with other known flaviviruses such as dengue and West Nile viruses. However, ZIKV's unique pathobiology demands an explanation of how its structure, although similar to its flavivirus relatives, is sufficiently unique to address questions of receptor specificity, transmission, and antigenicity. Progress in defining the immunodominant epitopes and how neutralizing antibodies bind to them will provide great insight as vaccines progress through clinical trials. Identification of host receptors will substantially illuminate the interesting ZIKV tropism and provide insights into pathogenesis. Although the answers to all of these questions are not yet available, rapid progress in combining structural biology with other techniques is revealing the similarities and the differences in virion structure and function between ZIKV and related flaviviruses.

Keywords: Zika virus; cryo-EM; maturation; neutralizing antibodies; receptors.

Figure 1.

Architecture of Zika virus (ZIKV) genomic ribonucleic acid (RNA), translation, and cleavage of ZIKV polyprotein, function, and localization of ZIKV proteins. The ZIKV genomic RNA is capped but it lacks a poly A tail. The gray lines represent 5’- and 3’-untranslated regions (UTR). The viral RNA codes for a polyprotein that is cotranslationally cleaved to yield 10 proteins. The 3 structural proteins (C, prM/M, and E) and 7 nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) are displayed with the length of each protein (number of amino acids). The cleavage profile of the polyprotein, the proteases involved, as well as the role and the subcellular location of individual proteins are provided in the figure. Information shown in the figure is true for flaviviruses in general, but many aspects need to be specifically verified for ZIKV. The figure does not provide an exhaustive list of the functions of each protein. The viral proteins interact with several host proteins, which expands their functional repertoire. The figure was created using Illustrator for Biological Sequences [103]. Abbreviations: aa, amino acid; ER, endoplasmic reticulum; LD, lipid droplet; nt, nucleotide; RC, replication complex; SP, signal peptide; TGN, Trans-Golgi Network; TMD, transmembrane domain.

Figure 2.

Structure of Zika virus (ZIKV). A–C depict the mature form of ZIKV (3.8 Å resolution) [1], whereas D–F represent the immature form (9.1 Å) [23]. Both mature and immature structures of ZIKV are centered on the 2-fold axis. A and D are surface-shaded, radially colored views of mature (EMD-8116) and immature ZIKV (EMD-8508), respectively. B and E are the respective cross-sections of A and D. Color coding is based on the key provided: red, up to 130 Å; yellow, up to 150 Å; green, up to 190 Å; cyan, up to 230 Å; blue, 250 Å and beyond. C displays the icosahedral arrangement and C_α-backbone of the E and M proteins derived from the 3.8 Å density map of mature ZIKV (Protein Data Bank [PDB] 5IRE). Two asymmetric units related by 180° define the raft subunit of the virus consisting of 3 pairs of E and M homodimers. F shows the C_α-backbone of the DENV2 prM-E heterodimer (PDB 3C6E) and transmembrane domains of ZIKV E and M proteins (PDB 5IRE) fitted into the immature ZIKV map (PDB 5U4W). E protein is colored as follows: domain I (red), II (yellow) with fusion loop in green, III (blue) and stem-transmembrane helices (pink). pr peptide is shown in purple. The soluble region of M protein is displayed in magenta, and the stem-transmembrane helices are represented in cyan. The glycans projecting from the surface on prM and E proteins are highlighted. The molecular graphics of ZIKV were made using the Chimera package developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081) [104].

Figure 3.

The maturation pathway for flaviviruses. The orchestrated conformational changes in viral surface glycoproteins (prM/M, E) and the proteolytic cleavage of prM protein by host protease furin in the secretory pathway that converts an immature, spiky, and noninfectious virus to a mature, smooth, and infectious virus. The asterisk indicates exceptions to the idea that immature viruses are noninfectious. The immature viruses can be rendered infectious if the furin cleavage site is intact and the entry of these virions is assisted by nonneutralizing antibodies. The furin cleavage is inefficient for dengue virus (DENV) due to a suboptimal cleavage site leading to morphogenetic diversity in the virus population. The efficiency of prM cleavage for Zika virus (ZIKV) remains unknown. The figure was generated using University of California, San Francisco chimera package from the Computer Graphics Laboratory, San Francisco [104]. The figure was created using the Chimera package developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco. The Protein Data Bank identification for the neutral pH immature DENV2 on the left is 3C6D, the low pH immature DENV2 is 3C6R, furin cleaved but pr-bound DENV2 at low pH is 3IYA, and the mature smooth DENV2 on the right is 1THD. DENV, instead of ZIKV, was used for the schematic because only the structures for immature and mature forms of ZIKV are available. The maturation pathway for ZIKV is expected to be similar to that of DENV. Abbreviations: ER, endoplasmic reticulum; TGN, Trans-Golgi Network.