This article is part of Harvard Medical School's continuing coverage of COVID-19.
- By STEPHANIE DUTCHEN
Researchers at Harvard Medical School and the University of Freiberg in Germany have captured the first, long-awaited snapshots at near-atomic resolution of B-cell receptors - intricate assemblages of proteins protruding from the surface of B cells that detect invaders such as viruses and bacteria and alert the cells to fight.
The resulting three-dimensional structure, described Oct. 13 in Nature and based on imaging of mouse B-cell receptors, promises to deepen scientists' understanding of how B cells function in health and disease. It also could advance efforts to thwart infections by pathogens such as SARS-CoV-2, improve vaccines, and develop new treatments for diseases that involve problems with B-cell receptors, such as some leukemias and lymphomas.
Receptors allow B cells to perform their most critical roles: producing antibodies and remembering how to fight specific pathogens long after an initial infection. But how exactly receptors latch onto potential dangers and kick B cells into action has been one of the holes in the understanding of B cell function.
Filling in those gaps requires revealing the tiniest details of what the receptors look like, both at rest and when they spring into action to attach to various molecules. It reflects a tenet of biology: structure illuminates function.
"Probing the structures of B cell receptors provides clues about how a virus such as SARS-CoV-2 can be detected or escape detection," said Ying Dong, research fellow in biological chemistry and molecular pharmacology in the lab of Hao Wu at HMS and Boston Children's Hospital and co-first author of the study.
"That is one reason why revealing these structures is important in the context of the ongoing COVID-19 pandemic," said Wu, professor of biological chemistry and molecular pharmacology in the Blavatnik Institute at HMS and the HMS Asa and Patricia Springer Professor of Structural Biology in the Program in Cellular and Molecular Medicine at Boston Children's Hospital. Wu is co-senior author of the paper with Michael Reth at the University of Freiburg.
Although the work was done with mouse B cell receptors, new and previous evidence raises the researchers' confidence that their findings will apply in humans. For instance, although the mouse receptor differs in some ways from the human one, key portions contain amino acid sequences that are "highly conserved" in our two species and many others, said Wu.
A tale of two halves
The researchers captured the structure of one type of B cell receptor using cryo-electron microscopy.
The receptor is known as IgM because its main components are immunoglobulin M antibodies. (The B cell receptor's four siblings are IgA, IgD, IgE, and IgG.) IgM antibodies are typically the first in the body to encounter and fight bacteria and viruses.
Piecing together hundreds of thousands of cryo-EM images revealed the subunits of the IgM receptor in unprecedented detail.
Among the team's findings was an answer as to how IgM is attached to the other part of all B cell receptors: a pair of proteins called Ig alpha and Ig beta. This pair extends inside the cell and sends an alert to the nucleus when the receptor captures something.
The scientists were surprised to find that IgM, which has two symmetric arms, connects to Ig alpha and Ig beta at only one of its sides, forming an overall asymmetrical shape. T cell receptors have similar asymmetry.
Until now, no one knew "exactly how these signaling subunits are connected with the immunoglobulin," said Reth.
The team was able to unveil a portion of the receptor that eluded scientists studying human B cells, Dong said.
The overall structure also suggests that other molecules act in concert with the B cell receptor in a larger complex.
"We only know part of the machine so far," said Reth.
The findings provide tantalizing hints that the other B cell receptor types will prove to have the same or similar structures.
What comes next
If the insights are confirmed in people, they could help scientists answer outstanding questions about how the receptor detects infectious agents and vaccines and instigates responses to them. Those answers, in turn, could drive efforts to fight or prevent infections that involve B cells.
"Vaccines, like pathogens, are initially recognized by B cell receptors," said Dong. "That could provide further guidance for developing potent vaccines."
Knowing the receptor's precise structure could help researchers develop drugs that increase or suppress B cell signaling to treat disease. In lymphoma, for example, B cell receptors signal uncontrollably.
The study dovetails with recent work by other researchers in the HMS Department of Biological Chemistry and Molecular Pharmacology that solved the structure of the B cell co-receptor, which turbocharges the B cell receptor.
Wu and colleagues already have their sights set on more. They want to discover the other molecules that attach to the receptor and to catch the receptor in action so they can learn more about what keeps it in a dormant state when dangers aren't around.
Funding and authorship
Dong is co-first author of the new paper with Xiong Pi in the Wu lab. Other co-authors are Frauke Bartels-Burgahn, Deniz Saltukoglu, and Jianying Yang of Freiberg University; Frederick Alt, professor of genetics in the Blavatnik Institute at HMS and the HMS Charles A. Janeway Professor of Pediatrics at Boston Children's; and Zhuoyi Liang of the Alt lab.
The findings were made possible in part by collaborations with the Harvard Cryo-EM Center for Structural Biology. The study was funded by the National Institutes of Health (grant R01AI145656) and by the German Research Foundation, or DFG (grant TRR130-P02).
Adapted in part from a University of Freiburg news release.
