3D shapes of viral proteins reveal previously unknown roles

Viruses are hard to track. They evolve rapidly and regularly develop new proteins that help them infect their hosts. These rapid changes mean that researchers are still trying to understand a multitude of viral proteins and how precisely they increase the viruses’ infectious abilities. This knowledge could be crucial to developing new or better treatments for viruses.

Now, a team of scientists from the Gladstone Institutes and the Innovative Genomics Institute, led by Jennifer Doudna, Ph.D., has used computational tools to predict the three-dimensional shapes of nearly 70,000 viral proteins.

The researchers matched the 3D shapes to protein structures whose functions are already known. Since the structure of a protein directly contributes to its biological function, their study provides new insights into the exact role of these lesser-known proteins.

Among their other findings, published in the journal NatureResearchers have discovered a powerful way for viruses to evade the immune system. In fact, they have found that viruses that infect bacteria and those that infect higher organisms, including humans, share a similar ancient mechanism for evading the host’s immune defenses.

“As viruses with pandemic potential emerge, it’s important to determine how they will interact with human cells,” said Doudna, who is also a professor at the University of California, Berkeley, and a Howard Hughes Medical Institute investigator. “Our new study provides a tool to predict what these newly emerging viruses might do.”

Sequence versus form

Typically, to determine the function of a protein, researchers look for similarities between its distinct sequence of “component” amino acids and the amino acid sequences of other proteins with known functions. However, because viruses evolve so rapidly, many viral proteins do not have significant similarities to known proteins.

However, just as different combinations of building blocks can be used to build very similar structures, proteins with different sequences can share 3D shapes and play similar biological roles.

“We looked at similarities between protein shapes as a promising alternative to determining viral protein function,” says Jason Nomburg, Ph.D., a postdoctoral researcher in Doudna’s lab at Gladstone and first author of the study. “We asked ourselves: What can we learn from protein structures that we might miss by looking at sequences alone?”

To answer this question, the team turned to an open-source research platform called AlphaFold, which predicts the 3D shape of a protein based on its amino acid sequence. They used AlphaFold to predict the shape of 67,715 proteins from nearly 4,500 species of viruses that infect eukaryotes (organisms including plants, animals, and humans that contain DNA in the nucleus of their cells). Then, using a deep learning tool, they compared the predicted structures to those of known proteins from other viruses, as well as to those of nonviral proteins from eukaryotes.

“This would not have been possible without recent advances in these types of computational tools that allow us to accurately and quickly predict and compare protein structures,” Nomburg says.

Unexpected connections

The team found that 38% of the newly predicted protein shapes matched already known proteins and found key connections between them.

For example, some of the newly predicted structures belong to the group of “UL43-like proteins,” which are found in human herpesviruses, including those that cause mononucleosis and chickenpox.

“These new viral proteins are strikingly similar to known nonviral proteins in mammalian cells that help transport the building blocks of DNA and RNA across membranes,” Nomburg says. “Prior to this work, we didn’t know that these proteins could function as transporters.”

The team also found matches between the newly predicted viral protein structures and the structures of other viral proteins. Most notably, the analysis revealed a strategy for evading host immune defenses that is widely shared by viruses that infect animals and viruses called phages that infect bacteria. This mechanism appears to have been conserved throughout evolution.

“We are entering a very interesting area, because there is growing evidence that innate immunity in complex organisms, including humans, resembles many types of innate immunity in bacteria,” Nomburg says. “We will study these evolutionary links further, because a better understanding of how our cells respond to viruses could lead to new approaches to strengthening antiviral defenses.”

In the meantime, the team has made public the 70,000 newly predicted viral protein structures, along with data from their new analyses. These resources could offer other researchers the opportunity to discover other structural connections between proteins, which would deepen our knowledge of how viruses interact with their hosts.

“From a disease control perspective, this work is exciting because it highlights possible new approaches to designing broadly effective antiviral therapies,” Doudna says. “For example, discovering common and conserved mechanisms by which viruses evade immunity could lead to the development of potent antivirals that are effective against many different viruses at once.”