Why is SARS-CoV2 such a protean virion?
Some viruses have a crystaline structure- a capsid that is absolutely uniform, dictated by the proteins that make it up in orderly arrays. The classic T4 bacteriophage is like that, and one of its features is that it stuffs its DNA contents into the capsid under extremely high pressure (20 atmospheres). That allows those contents to shoot out later with great force, into its victim- a bacterium with a strong cell wall. Coronaviruses and related influenza viruses are not like that at all. Their RNA contents are loosely collected, and the capsid assembled in cellular membranes, ending up with a variable, almost floppy, shape. The way into the next target cell is not via a physical power-injection system, but much more gently, by using one of the eukaryotic cell's several mechanisms for endocytosis to slip inside, and then veer off from the fate of being digested like food, and instead set up shop inside its own custom-made system of vesicles.
The coronavirus surface (envelope) is composed of only a few proteins- the spike (S) protein that sticks out and attaches to, and initiates fusion with, target cells; the envelope (E) protein, which is a minor helper towards the virus's final shape; and the membrane (M) protein, which makes up most of the envelope. E is not essential, and S is not essential at all for virus formation, but M is quite essential. It gathers in huge amounts at internal membranes (called ERGIC) in rafts in preparation for virus assembly. Meanwhile the N protein has bound to special sequences on the genomic RNA, forming a sort of chromosome. The genomic RNA also has a particular tail that can bind directly to M protein. It is M that really orchestrates the whole assembly process, binding to the genomic RNA, to N, to E, and to S proteins, not to mention membrane lipids.
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| Schematic of the coronavirus envelope structure. The spike (S) protein in light gray sticks outwards. The nucleocapsid (N) protein in dark gray organizes the strands of genomic RNA. The envelope (E) protein in yellow occurs occasionally to impose curviture on the envelope, encouraging it to adopt a spherical shape. And the membrane (M) protein in black forms the bulk of the envelope, binding to and organizing all the other components. These authors find that occasional M proteins (red) lack inward projections. |
Incidentally, a recent paper came out about influenza M protein, which plays a very similar role, except that influenza virions are even more variable, forming into both spheres and filaments. These authors were able to generate remarkable images of the influenza M protein forming into very regular filament arrays, seen in cross-section, below.
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| Filaments of M1 protein from influenza virus, see in cross-section, with a littering of half-helices lying about. The core of these filaments would be filled with infectious genomic RNA. Scale bar is 1000 nm. |
So- why so unstructured? First, the viral envelope is developed from cellular membranes, and the final virus envelope still has some amount of lipids from those membranes. These tend to be quite fluid, limiting the structural regularity that can be achieved. Also, since there is no need for pressurized injection to the target, there is no need to obsess about the virus container as a totally defined, rigid body. It is apparent, from the micrographs below, that virion volumes can vary substantially, at least two-fold, suggesting that sometimes two genomes can get packed into one virion, or even more. Where is the harm in that? Given some spread by aerosols, twice the virus dose is perhaps a reasonable tradeoff for a slightly bigger and less spread-able virion container.
Is M a target for the immune system or for vaccines? No, no one seems to care about it, since it is the S protein that is most exposed on the surface and the key for attaching to and infecting new cells. Yet all parts of the virus life cycle are interesting, and it is certainly possible that small molecule drugs directed against M could be highly disruptive, to virus assembly if not to already- formed virions. Drug targets or not, these proteins play a humble structural role, knitting together virions so that they can go out into the hostile world on a puff of air and survive a few hours, enough to enter new hosts incautious enough to be gabbing in enclosed spaces.
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| A comparison of virions grown without S protein (top) or with S protein (bottom). Nor is N protein required for virion formation, really. It is M that organizes everything. These experiments use another coronavirus, mouse hepatitis virus (MHV). |
