The three groups of rotaviruses that cause gastroenteritis in humans are called groups A, B and C, groups A and C mainly affect children and have the best characteristics. On the other hand, little is known about the tip of the virus spike protein, called the VP8 * domain, which mediates the transmission of the virus cells, group B, which mainly causes severe diarrhea in adults.
“Determining the composition of VP8 * in group B rotavirus is important because it will help us understand how the virus infects gastrointestinal cells and will design strategies to prevent and treat these infections that cause severe outbreaks of diarrhea,” said the author. B.V. Venkataram Prasad, Professor. 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 method has not been successful. The researchers then turned their attention to a recently developed artificial intelligence-based computer program called Alphafold 2.
“AlphaFold2 predicts the 3D structure of proteins based on their genetic sequence,” said Dr. Leah Hu, the first author and co-author of the book, an assistant professor of biochemistry and molecular biology at Baylor. “We knew that the protein sequence of rotavirus group B to VP8 * was about 10% similar to the sequence of rotavirus A and C to VP8 *, so we expected a difference in 3D structure. But we were surprised when AlphaFold2 predicted a 3D structure for VP8 * B. Which is not only completely different from the VP8 * domains of rotavirus A and C, no other protein has previously been identified as having this structure.
With this information in hand, the researchers returned to the lab bench and experimentally confirmed that the structure of VP8 * B predicted by ALphaFold2 actually matched the actual structure of the protein using X-ray crystallography.
How rotavirus infects cells
Previous studies have shown that rotavirus A and C infect cells using the VP8 * domain to bind to specific sugar components of histo-blood group antigens, including blood groups A, B, AB and O, which are present in many cells in the body. It has been suggested that histogroups may explain the ability of different rotaviruses to bind different sugars to antigens, some of which infect young children in particular, while others affect other populations. Unlike VP8 * A and VP8 * C, the sugar specifications of VP8 * B have not yet been identified.
“We tested VP8 * B against a spectrum of sugars and found that it could recognize N-acetylactosamine, a common sugar in many cells in the body that is not recognized by rotavirus A and C to VP8 *,” Hu said. “This type of 3D structure capable of binding sugar has not been described before.”
“I am thrilled to discover a new 3D protein structure. I look forward to studying how to infect new structure cells and how this process compares to rotavirus A and C, as well as the discoveries that will follow,” he said. Co-author Dr. Wilhelm Salmon, Postdoctoral Fellow Prasad Laboratory.
“Our lab has been collaborating with Dr. Prasad’s lab for many years to understand the importance of the sugar-binding virus in gastrointestinal infections,” said Dr. Mary Estes, co-author of the Foundation’s Android Chair. Cullen and Emeritus Baylor, professor of virology and microbiology, are members of the Dan L. Duncan Comprehensive Cancer Center in Estes Baylor. “We have not yet been able to detect the group B virus, but our lab will now try to propagate these adult viruses into our human organ system, a tiny model of the human gut that could help us investigate the process of entry and virus growth. It could lead to new therapies.” Which is still needed for the treatment of diarrhea.
“This innovative method of determining the 3D structure of a protein represents a significant advance in the field of structural biology,” Hu said.
“I’m excited about our discovery of a novel 3D protein structure from an evolutionary perspective. It explains how viruses can evolve by incorporating structurally distinct modules with similar functionality, but it’s amazing how this structure evolved into this group B rotavirus.” Prasad is a member of the Alvin Romanesky Chair of Biochemistry and Dan L. Duncan of the Comprehensive Cancer Center.
The authors acknowledge support from NIH grants AI36040, AI080656, and P30 DK56338, and the Robert Welch Foundation (Q1279). The Gulf Coast Consortium Pharmacology has been awarded the Interdisciplinary Training (TIPS) Program for Scientists (Grant No. T32 GM120011), a DOE Office of Science User Installation Contract (DE-AC02-05CH11231) and the National Institutional Institution. Of General Medical Science, Grant P30 GM124169-01.
Source of the story
Materials provided by Baylor College of Medicine. Original by Anna Maria Rodriguez, Ph.D. Note: Content can be edited for style and length.