The network of tiny subunits called omicron, which form proteins, are notorious for their ability to mutate. But a group of researchers at Duke University thought they’d find out why that was happening only by exploring those tiny subsets of homologous proteins.
“One reason we focused on the protein homologs, and they often just seemed like right-size objects in the end of the root of the problem, was because they’re the ones we see the most [difficult to analyze]” study co-author Mehmet Oksakci said. He’s an assistant professor of chemistry and biochemistry at Duke and led the research with Sarah Pourciau, a postdoctoral researcher in Oksakci’s lab.
Previous work into mutations of homologous proteins had focused on homologous proteins of mutations within a single protein, although the key clue for omicron genetic shifts can be seen outside the protein. Slight differences in one type of homologous protein can mean the new homologous protein doesn’t assemble correctly, something that happens sometimes on homologous proteins due to current cell mutations.
The paper, published in Nature Communications, revealed that homologous protein mutations can also lead to homologous protein changes that can happen outside the homologous protein and result in molecular changes in DNA that are wholly new. In the non-mutated case, the proteins are in disarray and can be disassembled. In the mutated case, the homologous protein of mutations is disrupted and the alterations occur.
“People who’ve looked at it before have only seen data that they could find in a relatively small part of the population … but here we looked at multiple mutants and three different ways of assembling these amino acids and different ways of folding them and specific mutations in three different parts of the molecular assembly,” Pourciau said. “That makes for a very different story.”
Without a way to handle mutations that affect a large number of proteins, whole classes of protein-based drugs are useless, Pourciau said. Research shows that over 70 percent of the gene-written proteins in the human body are homologous with one another, and so a diversity of mutations causes unnatural protein configurations.
“It’s not like for the most part, you can say if a protein has been mutated that’s a really good reason to get rid of it,” Oksakci said. “Something that once worked in your body could now be problematic because it’s not functional.”
Scientists worry that this could lead to clusters of proteins that have caused their connections to be severed, resulting in immune system reactions, disease, and memory disorders. And Pourciau said that’s exactly what researchers have already found in some types of cancer. Cancer cells with mutations that had previously been linked to inherited diseases were connected to newly diagnosed cancer patients and presented with the developmental defects. In one case, one of the mutations reversed a mutation that causes cancer.
It can be easier to parse proteins and find mutations, and that’s why the work is important, Pourciau said. “Molecular clues can lead to targets or inhibitors to respond to us, and you can keep looking for new things,” she said.
The work is an early step in an investigation of what proteins do with their mutations and how evolution drives these biological changes.