Domain II also contains the fusion peptide, a glycine-rich hydrophobic sequence that initiates fusion by insertion into the target cell membrane. Domain III comprises the immunoglobulin-like domain responsible for receptor binding. In addition to the dramatic conformational and translational changes that the E protein undergoes during the virion maturation process, it also changes conformation during membrane fusion.
The low pH of the endosome during infection triggers a conformational change which results in the formation of E homotrimers. In this arrangement, the fusion peptides are exposed and available to insert into cellular membranes.
Interestingly, the structure of the E protein was found to be very similar to the structure of the Semliki Forest virus E1 protein, the fusion protein of the alphaviruses. The structures of two flaviviruses, dengue and West Nile virus, have been solved by cryo-EM and image reconstruction techniques and have been shown to be similar Figure 1 b.
Figures 1 a and 1 b. This arrangement of the E proteins completely covers the surface of the virus, thus rendering the lipid bilayer inaccessible. Domain III of E protrudes slightly from the viral surface, allowing interaction with cell receptors. The membrane-spanning regions of E and M proteins form antiparallel helices while the stem regions are arranged parallel to the membrane. The immature virus particle exhibits a dramatically different glycoprotein organization compared to the mature virion.
These spikes are composed of trimers of prM-E heterodimers. The pr peptide covers the fusion peptide of E in this arrangement, similar to E2 covering E1 in alphaviruses, thus protecting it from premature fusion as the immature particle is transported through the acidic environment of the secretory pathway.
The NC is found below the viral envelope and is composed of a single copy of the genome RNA and multiple copies of the C protein. Cryo-EM reconstructions of the virion have shown that in contrast to the alphaviruses, there is no apparent organization to the flavivirus NC.
This may be because there is no direct interaction between the C proteins in the core and the glycoproteins in the viral envelope since the E and M proteins do not penetrate below the inner leaflet of the membrane. Furthermore, no NCs have been observed in the cytoplasm of infected cells and attempts to establish an in vitro assembly system analogous to the alphavirus in vitro assembly system have failed.
The lack of coordination between the C protein and the viral envelope proteins suggests that the assembly of virions is driven by the lateral interactions of the E and M proteins in the viral envelope and not by the C protein.
This is supported by the observation that flavivirus infections result in the production of noninfectious subviral particles which are composed of just the viral envelope E and M and the lipid bilayer. Thus, the flavivirus glycoproteins are sufficient to induce particle budding. Virus-induced membrane structures called vesicle packets, which are continuous with the ER membrane, are the sites of flavivirus replication and assembly Figure 3.
Within these structures the structural proteins are in intimate contact with the genome RNA. The C protein associates with the genome RNA via interactions between the positive charges distributed throughout the protein and the negatively charged phosphate backbone of the RNA.
It is not yet clear how the C protein specifically recognizes the genome RNA; unlike for alphaviruses, a packaging signal has not been conclusively identified for flaviviruses. Coupling between genome replication and assembly within the vesicle packets has been proposed as a mechanism to ensure the specific encapsidation of the genome RNA. The NC lacks a defined icosahedral structure as described above. Therefore, core formation is probably concomitant with the association of the C protein and RNA genome with the viral glycoproteins and budding into the ER lumen, thus giving rise to the immature particle Figure 3.
The immature virion is transported from the ER to the Golgi where the viral glycoproteins are post-translationally modified. The cleavage of the prM protein in the trans-Golgi network triggers the dramatic reorganization of the viral glycoproteins that results in the formation of the mature virion Figure 3. The mature virion is then released from the host cell by exocytosis. Flavivirus assembly. Flavivirus assembly occurs on ER-associated membranes known as vesicle packets.
The immature virion buds into the ER and is transported to the Golgi and trans-Golgi network. The glycoproteins are post-translationally modified as the immature virus is transported through the secretory pathway. Furin cleavage of prM results in the formation of the mature virus which then exits the cell by exocytosis. Following from the discussion of alphavirus and flavivirus assembly, it is apparent that the assembly of even the simplest enveloped viruses requires the complex interaction of viral and host factors in order to produce a virus particle which is at once stable and at the same time primed for disassembly.
The whole range of the cell's machinery including the translation apparatus, polymerases, chaperones, and post-translational modification enzymes are co-opted by viruses in order to replicate the viral components necessary for assembly. Enveloped viruses have evolved to utilize different cellular membranes and cellular compartments for assembly and they take advantage of the secretory pathway to produce their viral glycoproteins.
A majority of viruses bud from the plasma membrane Table 1. This is the case with alphaviruses, where NC assembly occurs in the cytoplasm and the final assembly of the mature virion occurs at the plasma membrane.
The high concentration of viral proteins, often concentrated at specific sites allows for the efficient interaction and assembly of virions. In contrast to alphaviruses, NC assembly and glycoprotein assembly is coupled in the flaviviruses and occurs in vesicle packets associated with the ER. Thus, the whole flavivirus virion is transported through the ER and Golgi while in the case of the alphaviruses only the glycoproteins are transported through the secretory pathway.
These exit strategies are not unique and thus serve as model systems to study enveloped virus assembly and release. Proteolytic cleavage of glycoproteins in order to convert them from stable oligomeric structures to metastable structures primed for fusion are common themes in enveloped virus structure and assembly. Cleavage of PE2 into E3 and E2 by a furin-like protease primes the alphavirus spike complex for fusion. A similar cleavage of prM triggers a dramatic conformational change of the flavivirus glycoproteins resulting in the formation of the mature virion which is now infectious.
Alphavirus budding requires the specific interaction of the NC with the E1—E2 spike complexes at the plasma membrane, thus ensuring that all virions have a genome packaged into them.
However, the flaviviruses only require the interaction of the envelope proteins for budding, giving rise to subviral particles devoid of the C protein and genome RNA. Thus, the flavivirus envelope proteins alone are sufficient to drive budding of virus particles and the close coupling of genome replication and the C protein perhaps mediated by replication proteins and host factors is required to package the genome into virus particles.
A third strategy for budding is exhibited by the retroviruses where capsid assembly has been shown to be sufficient to drive budding of the virus. In this case, targeting of the envelope proteins to these sites of CP assembly is essential to ensure the incorporation of the glycoproteins into the virion. Although much has already been discovered about enveloped virus assembly, there are still many processes yet to be described. There is an increasing interest in the assembly pathway of viruses partly fueled by the potential to develop successful therapeutic agents targeting virus specific assembly processes.
Advances in the field of structural biology will further help attempts to understand the assembly pathway of this important class of viruses. National Center for Biotechnology Information , U. Encyclopedia of Virology.
Published online Jul Navaratnarajah , R. Warrier , and R. Guest Editor s : Brian W. Guest Editor s : Marc H. Author information Copyright and License information Disclaimer. All rights reserved. Elsevier hereby grants permission to make all its COVIDrelated research that is available on the COVID resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source.
Abstract Viruses can be broadly categorized based on the presence, or absence, of a lipid envelope in their structure. Introduction Viruses have long been distinguished by their physical features, usually visualized by electron microscopy or analyzed biochemically.
Table 1 List of enveloped virus families and the origin of the envelope. Open in a separate window. Viral Envelope The main component of the viral envelope is the host-derived lipid bilayer. Icosahedral Enveloped Viruses: Alphaviruses and Flaviviruses Alphaviruses, and more recently, flaviviruses have served as model systems to study the assembly and budding of simple enveloped viruses. Alphavirus Assembly Alphavirus life cycle Alphaviruses are members of the family Togaviridae , which also includes the genus Rubivirus.
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Biomedical Citizen Science. Director's Message. Budget Proposal. Stories of Cancer Research. Members of the family Picornaviridae , which include Hepatitis A virus, poliovirus, and Coxsackieviruses, have non-enveloped particles that consist of a protein shell surrounding the viral RNA genome poliovirus is illustrated.
Examples of viruses that are enveloped include dengue virus, influenza virus , and measles virus. Recently it was discovered that hepatitis A virus HAV particles are released from cells in membrane vesicles containing virus particles.
These membranous structures resemble exosomes, which are also released from uninfected cells and play roles in various biological processes. Enveloped hepatitis A virus particles are present in the blood of infected humans. However virus in the feces, which is transmitted to other hosts, is not enveloped. Viral envelopes typically contain viral glycoproteins, such as the HA protein of influenza viruses, which serve important functions during replication, such as attachment to cell receptors.
Envelope glycoproteins are also the target of antibodies that block viral infection. The presence of an envelope makes HAV resistant to neutralization with antibodies, because the membrane contains no viral proteins that can be blocked by antibodies. Two other non-enveloped picornaviruses, Coxsackievirus B and poliovirus , are also released from cells within membrane vesicles.
These virus particles are in vesicles derived from the autophagy pathway, which captures and recycles cytoplasmic contents by ejecting them from the cell.
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