Credit: Rhoda Baer
Researchers say they have discovered a bacterial protein that attaches to virtually any antibody and prevents it from binding to its target.
It appears that this molecule, called mycoplasma protein (or protein M), helps some bacteria evade the immune response and establish long-term infections.
The researchers discovered protein M in samples from multiple myeloma (MM) patients.
And the team believes the protein could be engineered to target cancerous B cells in patients with MM and other B-cell malignancies.
Protein M might also become a target for new antibacterial drugs, and it could prove useful for preparing highly pure antibodies for research and drug manufacturing.
Richard A. Lerner, MD, of The Scripps Research Institute (TSRI) in La Jolla, California, and his colleagues described their discovery of protein M in Science.
The discovery originated from an effort to understand the origin of MM. Clonal B-cell proliferation, as well as MM and lymphomas, can result from chronic infections by organisms such as Escherichia coli, Helicobacter pylori, and hepatitis C virus.
To better understand this process, Dr Lerner and his colleagues investigated mycoplasma, a parasite that infects people chronically and is largely confined to the cell surface.
In a search for factors associated with long-term mycoplasma infection, the team tested samples of antibodies from MM 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.
To the researchers’ surprise, every antibody sample tested showed reactivity to this protein. But further tests made it clear that these antibody reactions were not in response to mass infection with M genitalium.
Instead, the M genitalium protein, which the team named protein M, appeared to have evolved simply to bind to any antibody it encounters.
“It binds to every antibody generically—capable of hijacking the entire diversity of antibody repertoire—but, at the same time, it blocks the specific interaction between that antibody and its intended biomolecular target,” said Rajesh Grover, PhD, of TSRI.
To better understand how protein M works, the researchers took a structural biology approach. Using X-ray crystallography and other techniques, the team determined the protein’s 3D atomic structure while it was bound to various human antibodies.
Compared to thousands of known structures in the Protein Data Bank, the worldwide structure database, protein M appeared to be unique. The data also revealed that protein M binds to a small, conserved region at the outer tip of every antibody’s antigen-binding arm.
“It likely extends the other end of itself, like a tail, over the antibody’s main antigen-binding region,” said Xueyong Zhu, PhD, of TSRI.
The team is now studying protein M’s function during M genitalium infections. It seems likely that the protein evolved to help M genitalium cope with the immune response, as it has one of the smallest bacterial genomes in nature.
“It appears to represent an elegant evolutionary solution to the special problem that mycoplasma have in evading the adaptive immune system,” Dr Grover said. “The smallest parasitic [bacterium] on planet Earth seems to have evolved the most sophisticated invading molecular machine.”
If protein M is confirmed as a universal “decoy” for antibodies, it will become a target for new drugs, the researchers said. This could make it easier to treat chronic, sometimes silent, infections by M genitalium and any other microbes that have evolved a similar antibody-thwarting defense.
In principle, protein M also could be engineered to target specific groups of B cells, delivering cytotoxic agents to cancerous B cells in patients with MM and lymphomas.
But the most immediate use of protein M, according to the researchers, is likely to be as a tool for grabbing antibodies in test tubes and cell cultures. This would allow the preparation of highly pure antibodies for research and drug manufacturing. Other generic antibody-binding proteins have been put to use in this way, but, so far, it appears that none does the job quite as well as protein M.
“It may be the most useful antibody purification device ever found,” said Dr Lerner, who is now working to commercialize the protein.
