AI reveals a 3D structure never before described in the spike protein of a rotavirus

Of the three groups of rotaviruses that cause gastroenteritis in humans, called groups A, B and C, groups A and C mainly affect children and are the best characterized. On the other hand, from group B, which mainly cause severe diarrhea in adults, little is known about the tip of the spike protein of the virus, called the VP8* domain, which mediates cell infection of the virus.

The corresponding author, Dr. with me. in. Venkataram Prasad, Professor. of Biochemistry and Molecular Biology at Baylor College of Medicine.

The team’s first step was to determine the 3D structure of VP8*B using X-ray crystallography, a time-consuming and laborious process. However, this traditional approach did not work in this case. The researchers then turned to a recently developed AI-based computer program called AlphaFold2.

“AlphaFold2 predicts the three-dimensional structure of proteins based on their genetic sequence,” said first author and corresponding co-author Dr. Leah Hu, associate professor of biochemistry and molecular biology at Baylor. “We knew that the protein sequence of VP8* from rotavirus group B was about 10% similar to that of VP8* from rotavirus A and C, so we also expected differences in 3D structure. But we were surprised when AlphaFold2 predicted a 3D structure of VP8*B It was not only completely different from the VP8* domain in rotavirus A and C, but also no other protein had previously been characterized as having this structure.

With this information in hand, the researchers returned to the lab table and experimentally confirmed that the structure of VP8*B predicted by ALphaFold2 indeed matches the actual structure of the protein using X-ray crystallography.

How does rotavirus infect cells?

Previous research has shown that rotaviruses A and C infect cells using the VP8* domain to bind to specific sugar components of blood type antigens, including blood groups A, B, AB and O found in many cells of the body. It has been suggested that the ability of different rotaviruses to bind different sugars to histogroup antigens could explain why some of these viruses specifically infect young children while others affect other populations. In contrast to VP8*A and VP8*C, the sugar specificity of VP8*B has not been characterized so far.

“We examined VP8*B against a spectrum of sugars and found that it recognizes N-acetyllactosamine, a common sugar in many cells of the body that VP8* does not recognize from rotavirus A and C,” Hu said. “Such a three-dimensional structure capable of binding sugar has not been previously described.”

“I am pleased to have identified a new 3D protein structure. I also anticipate all the discoveries that will follow as we study how the new structure interacts with cells to infect them and how this process compares to that of rotaviruses A and C,” said co-author Dr. Wilhelm. Salmen, Postdoctoral Fellow in Prasad’s Laboratory.

“Our lab has collaborated with Dr. Prasad’s lab for many years to understand the importance of diabetes-related viruses in gastrointestinal infections,” said co-author Dr. Mary Estes, chair of the talent foundation. Cullen is Professor Emeritus of Virology and Microbiology at Baylor. Estes is also a member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “We cannot grow group B virus yet, but our lab will now attempt to grow these adult viruses in our human organ systems, a miniature model of the human intestine that could help us investigate the virus’s entry and growth mechanism. It may lead to new therapies still needed to treat diarrheal diseases. . »

“This new approach to determining the three-dimensional structure of a protein represents an important advance in the field of structural biology,” Hu said.

“I am excited about our discoveries of a new 3D protein structure from an evolutionary perspective. This shows how viruses can evolve by incorporating structurally distinct units with similar functions, but how this structure arose in this group B of rotavirus is very interesting,” said Prasad, president of Department of Biochemistry Alvin Romansky and member of the Dan L. Duncan Comprehensive Cancer Center.

The authors acknowledge support from National Institutes of Health grants AI36040, AI080656, P30 DK56338, and the Robert Welch Foundation (Q1279). Additional support was provided by the Gulf Coast Consortium (TIPS) Interdisciplinary Training of Scientists in Pharmacology Program (TIPS) (grant number T32 GM120011), the Department of Energy Office of Science User Installation Contract (DE-AC02-05CH11231) and the National Institutes of Health, National Institute of General Medical Sciences Grant P30 GM124169-01.

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Material provided by Baylor College of Medicine. Original by Ana Maria Rodriguez, Ph.D. Note: Content can be modified according to style and length.

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