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. 2005:64:165-230.
doi: 10.1016/S0065-3527(05)64006-7.

Molecular interactions in the assembly of coronaviruses

Cornelis A M de Haan  1 , Peter J M Rottier
Affiliations

Molecular interactions in the assembly of coronaviruses

Cornelis A M de Haan et al. Adv Virus Res. 2005.

Abstract

This chapter describes the interactions between the different structural components of the viruses and discusses their relevance for the process of virion formation. Two key factors determine the efficiency of the assembly process: intracellular transport and molecular interactions. Many viruses have evolved elaborate strategies to ensure the swift and accurate delivery of the virion components to the cellular compartment(s) where they must meet and form (sub) structures. Assembly of viruses starts in the nucleus by the encapsidation of viral DNA, using cytoplasmically synthesized capsid proteins; nucleocapsids then migrate to the cytosol, by budding at the inner nuclear membrane followed by deenvelopment, to pick up the tegument proteins.

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Figures

Fig 1
Fig 1
Electron micrographs of mouse hepatitis virus strain A59 (MHV‐A59) virions without (A) and with (B) the hemagglutinin‐esterase (HE) envelope protein (viruses kindly provided by R. de Groot, Virology Division, Utrecht University, The Netherlands; image courtesy of J. Lepault, VMS‐CNRS, Gif‐sur‐Yvette, France). Large, club‐shaped protrusions consisting of spike (S) protein trimers give the viruses their corona solis‐like appearance. Viruses containing the HE protein display a second, shorter fringe of surface projections in addition to the spikes. (C) Schematic representation of the coronavirion. The viral RNA is encapsidated by the nucleocapsid (N) protein forming a helical ribonucleoprotein (RNP), which is in turn part of a structure with spherical, probably icosahedral, configuration. The nucleocapsid is surrounded by a lipid bilayer in which the S protein, the membrane glycoprotein (M), and the envelope protein (E) are anchored. In addition, some group 2 coronaviruses contain the HE protein in their lipid envelope as illustrated on the right side of the particle.
Fig 2
Fig 2
The coronavirus life cycle. The replication cycle starts with attachment of the virion by its S protein, that is, through the S1 subunit thereof, to the receptors on the host cell. This interaction leads to fusion of the virus envelope with a cellular membrane, for which the S2 subunit is responsible. From the genomic RNA that is released by disassembly of the incoming particle the pol1a and pol1b genes are translated, resulting in the production of two large precursors (Pol1a and Pol1ab), the many cleavage products of which collectively constitute the functional replication–transcription complex. Genes located downstream of the pol1b gene are expressed from a 3′‐coterminal nested set of subgenomic (sg) mRNAs, each of which additionally contains a short 5′ leader sequence derived from the 5′ end of the genome (shown in red). Transcription regulatory sequences (TRSs) located upstream of each gene serve as signals for the transcription of the sgRNAs. The leader sequence is joined at a TRS to all genomic sequence distal to that TRS by discontinuous transcription, most likely during the synthesis of negative‐strand sgRNAs. In most cases, only the 5′‐most gene of each sgRNA is translated. Multiple copies of the N protein package the genomic RNA into a helical structure in the cytoplasm. The structural proteins S, M, and E are inserted into the membrane of the rough endoplasmic reticulum (RER), from where they are transported to the ER‐to‐Golgi intermediate compartment (ERGIC) to meet the nucleocapsid and assemble into particles by budding. The M protein plays a central role in this process through interactions with all viral assembly partners. It gives rise to the formation of the basic matrix of the viral envelope generated by homotypic, lateral interactions between M molecules, and it interacts with the envelope proteins E, S, and HE (if present), as well as with the nucleocapsid, thereby directing the assembly of the virion. Virions are transported through the constitutive secretory pathway out of the cell—the glycoproteins on their way being modified in their sugar moieties, whereas the S proteins of some but not all coronaviruses are cleaved into two subunits by furin‐like enzymes (see text for references).
Fig 3
Fig 3
Coronavirus genome organization as illustrated for the group 2 virus MHV. The single‐stranded, positive‐sense RNA genome contains 5′‐ and 3′‐terminal untranslated regions (UTRs) with a 5′‐terminal cap and a 3′‐terminal poly(A) tract. The leader sequence (L) in the 5′ UTR is indicated. All coronaviruses have their essential genes in the order 5′‐pol‐S‐E‐M‐N‐3′. The pol1a and pol1b genes comprise approximately two‐thirds of the genome. The more downstream pol1b gene is translated by translational readthrough, using a ribosomal frameshift mechanism. Transcription regulatory sequences (TRSs) located upstream of each gene, which serve as signals for the transcription of the subgenomic (sg) RNAs, are indicated by circles. The genes encoding the structural proteins HE, S, E, M, and N are specified. Gray boxes indicate the accessory, group‐specific genes, in the case of group 2 coronaviruses genes 2a, HE, 4, 5a, and I.
Fig 4
Fig 4
Membrane topology of the coronavirus envelope proteins. The HE and S proteins are both type I membrane proteins, with short carboxy‐terminal cytoplasmic tails. The HE protein forms disulfide‐linked homodimers, whereas the S protein forms noncovalently linked homotrimers. The S1 subunits presumably constitute the globular head, whereas the S2 subunits form the stalk‐like region of the spike. The M protein spans the lipid bilayer three times, leaving a small amino‐terminal domain in the lumen of intracellular organelles (or on the outside of the virion), whereas the carboxy‐terminal half of the protein is located on the cytoplasmic side of the membrane (or inside the virion). In TGEV virions some of the M proteins have their cytoplasmic tail exposed on the outside (not shown). The M protein is glycosylated at its amino terminus (indicated by a diamond). The amphipathic domain of the M protein is represented by an oval. The hydrophilic carboxy terminus of the E protein is exposed on the cytoplasmic side of cellular membranes or on the inside of the virion. The E protein may span the bilayer once (b) or twice (a).
Fig 5
Fig 5
Structural maturation of coronavirus particles. Two types of virion‐related particles were detected in TGEV‐infected cells. Although large virions with an electron‐dense internal periphery and a clear central area are abundant at perinuclear regions, smaller viral particles, with the characteristic morphology of extracellular virions, accumulate inside secretory vesicles that reach the plasma membrane. (A) Large virions (arrowheads) and small dense viral particles (arrows) coexist within the Golgi complex of infected cells (Risco et al., 1998). (B) For a direct comparison of size and morphology a small, dense particle and a large particle are shown (Salanueva et al., 1999). Pictures were kindly provided by C. Risco.
Fig 6
Fig 6
Structural organization of the coronavirus N protein. Common features and their distribution along the polypeptide chain are shown schematically. The hatched box indicates the most conserved part of the N protein, with a high proportion of aromatic residues. The N protein contains many basic residues throughout the polypeptide, but with particular clustering in two regions (+++). The upstream cluster contains a serine/arginine‐rich region (S/R). The carboxy terminus, which contains a high proportion of acidic residues, is also indicated (−−−). The bars indicate parts of the N protein that have been implicated in N–N and N–RNA interaction. Furthermore, the location of the deletion in the MHV‐A59 mutant Alb4 (Δ) is indicated as well as the domain where second‐site mutations in revertant viruses of Alb4 are mapped. Finally, the parts of the N protein that could not be transferred from BCV into the MHV genome are marked. References are included in the figure.
Fig 7
Fig 7
The various domains of the MHV M protein and the processes for which they are important. The amphipathic domain of the M protein is represented by an oval. See text for references.
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