The discovery of “the second type of massively variable protein ever” by the University of California, San Diego researchers, can open new doors in the development of novel protein drugs. This is how:
“This is only the second type of massively variable protein ever discovered,” explained Partho Ghosh, a professor of chemistry and biochemistry at UCSD who headed the research team. “Only antibodies have more variation than this protein in phage. However, the genetic mechanism used by the phage to generate this diversity is completely different from that used by animals to produce antibodies, and has the advantage of giving the protein greater stability.”
“If we can learn from these organisms how to set up a system that churns out proteins with enormous variability, it may be possible to target these new proteins to specific cells to treat disease,” said Stephen McMahon, a former postdoctoral fellow in Ghosh’s lab who conducted much of the research. “This idea has already been picked up by the biotech industry.”
The function of the massively variable phage protein is to tether the phage to the bacteria they infect. The phage “predator” protein fits into a “prey” protein on the bacteria like a three-dimensional puzzle piece. However, the bacteria are constantly changing the proteins on their surface. To keep up with the unpredictable changes in the prey protein, the phage must generate many different predator proteins for at least one to have an acceptable fit.
In their paper, the researchers describe how by altering the amino acids at one or more of just 12 sites on the predator protein, the phage are able to generate 10 trillion proteins, each with the potential to bind to a different prey protein. This variability arises as DNA is being copied into the RNA blueprint for the protein. The sequence of DNA bases at the 12 sites has unique characteristics that cause frequent mistakes to be made in the copying process. As a result, the RNA ends up specifying a different amino acid, and a protein with different structural and chemical properties is created.
Antibodies are another type predator protein that must respond to rapidly evolving prey proteins, because microorganisms are constantly altering proteins on their surfaces to evade the immune system. Unlike the phage protein, antibodies have a complicated loop structure. The size of the loops varies in addition to the amino acid building blocks that constitute the antibody protein. Although this mechanism can generate more than 100 trillion different antibodies, the researchers say replicating it in a test tube would be very challenging because the loops would have the tendency to fold incorrectly.
“Because of its stability, the phage protein makes a better model to create protein diversity in a test tube,” explained Jason Miller, a graduate student in Ghosh’s lab who conducted much of the research. “Our discovery shows that nature has provided at least two completely different methods to generate a huge amount of protein variability, and it opens up a whole new platform for protein development.”
The press release…