VIRUSES HAVE BELLYBUTTONS
Researchers are rethinking models that depict viruses as perfectly symmetrical. ROBERT LAWRENCE reports.
The imperfections of nucleic acid molecules in protein coats.
WHILE MOST PEOPLE would not think of a virus as a beautiful manifestation of nature, scientists who map their molecular shape and structure are more easily smitten.
Like the 20 white hexagons and 12 black pentagons of a soccer ball, some viruses consist of a set number of repeating protein units that form an ordered, symmetrical and almost spherical nanoshell around their genome.
In the past 40 years, scientists in the field of structural biology have developed hundreds of beautiful three-dimensional computer models of such viruses. Often, the details of their composition are mapped down to individual atoms.
In addition to visualising the stunning order and symmetry of a virus particle on an atomic scale, these models help researchers understand how viruses assemble, infect and propagate within
their host. But according to a new study by a group of researchers at Purdue University in Indiana, US, some aspects of these models may not be entirely realistic.
Their data show that some types of viruses have a break in their symmetry that standard models don’t show. These asymmetries may reveal new details about the life cycle of those viruses.
In 1956 – only a few years after they announced the structure of DNA – Francis Crick and James Watson described their theory that viruses can have a symmetrical structure made of repeating protein units. As with the discovery of the double helix, their thinking was informed by Rosalind Franklin’s prior work on virus structures; and their thinking was correct.
Although not all viruses have a geometric shape, we know now that a lot of them do. A common one that many unrelated groups share is that of an icosahedron – a polygon with 20 sides and 12 vertices. The form is defined by a set number of protein units in their outer shell.
The same year that Crick and Watson published their ideas on virus structure, a young student by the name of Michael Rossman was completing his PHD at Scotland’s University of Glasgow in chemical crystallography – the science of making a given sample crystallise so that its structure can be probed with a beam of X-rays and the mathematics of how those X-rays diffract.
Also known as X-ray crystallography, this approach is useful with all kinds of molecules, including DNA, proteins and even whole viruses that have a defined shape. This last case is what eventually captured Rossman’s interest.
The scientist has been at Purdue University since 1964, building what is probably the world’s leading research program in the investigation of virus structures with X-ray crystallography and related techniques. At the age of 88, he exudes a remarkable acuity that remains salient among his academic peers. Foremost among them is virologist Richard Kuhn.
Since joining Purdue in 1992, Kuhn has partnered with Rossman on mapping a few dozen virus structures. Rossman and Kuhn were the first to report the structure of the Zika virus a few years ago – just as it was emerging into the public consciousness.
Rather than X-ray crystallography, they used a newer technique to do this that has become increasingly useful in the field of structural biology. Cryo-electron microscopy, as it is known, can produce high-resolution images of individual virus particles in a frozen state from a beam of electrons.
Recently, while pouring over some cryo-electron microscopy images of a West Nile virus strain bound to an antibody, one of Kuhn’s graduate students noticed something unusual.
“There was a fuzzy density on just one side of the virus,” Matthew Therkelsen recalls. “That signified to me that there was a distinct feature in the virus structure, which is not predicted by symmetry.”
A typical model of the West Nile virus will have a neatly symmetrical arrangement of 180 protein units in its icosahedral shell. But the fuzzy patches Therkelsen was seeing in his data made him question that model.
“That was the first time I considered that the virus might be asymmetric,” he says.
Working with the rest of the team at Purdue, Therkelsen began plugging his data into computer models of the virus that did not rely on the assumption that the shape is perfectly symmetrical. The data aligned with those models and revealed that, in reality, the average West Nile virus may be a few protein units shy of the 180 that it takes to make it perfectly symmetrical.
Kuhn believes that this imperfection is probably an artefact of the last step of virus formation, when a new virus particle separates from the membrane of a cell that was infected by the previous generation.
“The neck of this budding particle gets very narrow as it pinches off and the glycoproteins surrounding the shell begin hitting one another,” Kuhn explains. “We think they might not grab the right number of proteins to make an icosahedron, and the result is a particle that has a distortion on one side.”
In other words, the break in symmetry is a lot like a belly button. And as such, it is a feature that is probably common to other viruses similar to West Nile. This includes the Zika, dengue, yellow fever and Chikungunya viruses – some of the most feared pathogens that humans can get from the bite of a mosquito.
Kuhn notes that other icosahedral viruses, such as polio and common cold viruses, may also have this asymmetry. “[It] is an intriguing question that we are also pursuing,” he says.
This scenario is likely. Structural biologist Sarah Butcher of the University of Helsinki, Finland, who was not involved in this study, noted that evidence of asymmetries in other virus structures has been seen in previously published work by her and other researchers.
“We wrote a couple of papers on how to deal with such asymmetry, and what were some of the reasons for it,” she says.
Along with researchers like Butcher, the team at Purdue has also found other asymmetries deeper within the anatomy of the West Nile virus that change during its development and may be related to asymmetry in the protein shell.
As evidence that icosahedral viruses aren’t perfectly symmetrical builds, researchers are becoming more curious about what these anomalies can tell us about life cycle. For instance, in addition to being a mark from the final point of assembly for a virus particle, they may also function to orient the virus during the initial point of infection when it releases its genome upon entering its host cell.
As such questions are investigated further, scientists like Rossman, Kuhn and Butcher may have cause to reconsider their assumptions about symmetry.
“Up until now,” Rossman says, “any such viruses that have ever been examined have been looked at with the assumption that they had icosahedral symmetry.”