Antibodies are precision weapons that attack specific targets. If any single target were capable of attracting any and all antibodies, other targets, in all their diversity, would enjoy a kind of shield. And every antibody occupied by the generic, all-purpose target would fail to bind to its intended target. It would, in a sense, be wasted.
A generic antibody-binding target actually exists. It’s a protein called protein M. (The “M” stands for mycoplasma.) It was discovered almost by accident by scientists investigating possible connections between long-term infections and cancer. The scientists, based at The Scripps Research Institute (TSRI), were working to understand the origins of multiple myeloma, a B-cell carcinoma. Clonal B-cell proliferation, as well as lymphomas and myelomas, can result from chronic infections caused by a variety of pathogens.
To better understand this process, the team investigated mycoplasma, a parasite that infects people chronically and is largely confined to the surface of cells. In a search for factors associated with long-term mycoplasma infection, Rajesh Grover, Ph.D., a senior staff scientist in the Lerner laboratory, tested samples of antibodies from multiple myeloma patients’ blood against a variety of mycoplasma species. One of the proteins recognized by the antibodies was from Mycoplasma genitalium, which causes sexually transmitted infections in humans.
To the scientists’ surprise, protein M reacted with every antibody sample tested. Additional tests established that these reactions were not in response to mass infection with M. genitalium. Instead, the scientists found, protein M appeared to have evolved simply to bind to any antibody it encounters.
Their interest piqued, the scientists investigated protein M’s structural biology via X-ray crystallography, electron microscopy, and other techniques. They found that protein M is unlike any of the known structures in the Protein Data Bank, a worldwide structure database. Moreover, they determined that protein M binds to a small, conserved region at the outer tip of every antibody’s antigen-binding arm.
Once protein M binds to an antibody, said Xeyong Zhu, Ph.D., a member of the TSRI team, “it likely extends the other end of itself, like a tail, over the antibody’s main antigen-binding region.”
The TSRI team published its findings February 6 in Science, in an article entitled “A Structurally Distinct Human Mycoplasma Protein that Generically Blocks Antigen-Antibody Union.” In this article, the authors speculate that protein M evolved to help M. genitalium cope with the immune response despite having one of the smallest bacterial genomes in nature. They also detailed how protein M binds to antibodies “with either κ or λ light chains using conserved hydrogen bonds and salt bridges, from backbone atoms and conserved side chains, and some conserved van der Waals interactions as well as other nonconserved interactions.”
Looking ahead, the authors explained that protein M—which they emphasize is a broad-scope, high-affinity antibody-binding protein—is likely to find myriad applications in immunochemistry. “Protein M,” they wrote, “may be particularly important for large-scale purification of therapeutic antibodies.”