The planet is crawling with exotic microorganisms, but what interests Assistant Professor of Chemistry Jacob Goldberg is an ordinary bug that’s right under our noses. Or, often, inside them.
Thirty percent of people have Staphylococcus aureus bacteria living in their nostrils, according to the Centers for Disease Control and Prevention.
“We feel like everything that we should possibly be able to know about this, we already do,” Goldberg says of the staph bacterium. “But that’s not the case.”
Staph bacteria usually coexist peacefully with people. But sometimes they can cause dangerous infections, especially in hospitals. One of the weapons in staph’s arsenal is a unique protein that the bacteria manufacture. In a recent paper published in Proceedings of the National Academy of Sciences, Goldberg and his co-authors investigated the structure of that protein. They say that a better understanding could ultimately help humans fight back when staph turns against us.
Proteins are large, complex molecules that living things use to build tissues and perform important tasks. Proteins start out as long chains of small molecules called amino acids. Then those chains twist and bunch to form three-dimensional shapes. The shape of a protein is critical to the job it does.
As part of their overall shape, many proteins include a twisted structure called an alpha helix, which resembles an old-fashioned landline telephone cord. Another common structure, called a beta sheet, looks like a pleated piece of paper.
Staphylococcus aureus bacteria make a family of proteins called phenol soluble modulins, or PSMs. In recent years, scientists discovered that one of these proteins, called PSM-alpha-3, has a unique shape. Its long fibers are built of out of alpha helices stacked together.
This so-called cross-alpha structure is a bizarre way to build a protein, Goldberg says. “It’s a really strange thing, the structure that the peptide adopts.”
Goldberg and University of Notre Dame co-author Arnaldo Serrano started talking about this weirdly constructed staph protein and wondered if they could join forces to learn more about how it takes shape. “We decided to work together to see what we could find,” Goldberg says.
In Goldberg’s lab, Vincent Betti ’21 worked on building PSM-alpha-3 proteins. Rather than harvesting molecules made by living Staphylococcus aureus bacteria, he assembled the proteins from scratch, out of amino acids. Then Goldberg sent these artificial PSM-alpha-3 proteins to Serrano’s lab.
There, Serrano used a tool called two-dimensional infrared spectroscopy to look at the proteins in detail. “This is not an easy technique,” Goldberg says; most labs aren’t set up for this type of extremely precise measurement. With two-dimensional infrared spectroscopy, Goldberg says, “you are able to diagnose exactly what’s happening at this molecular level, just by shining a light on it.”
The researchers confirmed that the unusual PSM-alpha-3 protein has a unique spectroscopic signature, which was “gratifying,” Goldberg says. They also saw that there’s more than one way staph bacteria can build the unusual shape.
The results help scientists “understand what’s happening in a very fundamental way,” Goldberg says.
Eventually, Goldberg hopes that gaining knowledge about PSM-alpha-3 and its related proteins will help scientists figure out how to fight dangerous staph infections. In nature, and in their interactions with humans, Staphylococcus aureus bacteria can form a kind of slimy, stubborn layer called a biofilm. Staph biofilms are a particular problem in hospitals; they can grow on the surfaces of medical devices such as catheters or pacemakers and may be resistant to antibiotics.
Research by other scientists has shown that the PSM-alpha-3 protein acts as a scaffold for the biofilm. In other words, it’s a kind of construction material for staph bacteria that are moving into a new setting (or patient) and trying to build themselves a sturdy home.
“The more we understand about how PSM-alpha-3 aggregates and binds together, the more we can start using this knowledge to think about ways to disrupt this in a clinical setting,” Goldberg says.
Biofilms aren’t the only sticky protein aggregations that pose a problem for humans. Clumps of protein in the brain are associated with Alzheimer’s disease and Parkinson’s disease. Goldberg studied the proteins linked to these neurodegenerative illnesses in graduate school.
Today, he’s focusing on other topics in brain science. He’s especially interested in the mysterious role that zinc plays in the brain.
Zinc ions are most common in the hippocampus, Goldberg says — a part of the brain involved in memory and learning — as well as in brain regions involved in our senses of hearing and smell. Zinc seems to have a role in how our brains process sound, and Goldberg is working with collaborators to learn more about what that role is.
In general, what excites Goldberg is talking with various kinds of scientists — biophysicists, neuroscientists — about compelling, unanswered questions in their fields. Then he thinks about how to build molecular tools in his lab, such as artificial staph proteins, to help investigate those topics.
“We have a number of different projects looking at big questions in biology, big questions in neuroscience,” Goldberg says. If answering those big questions requires a tiny, molecular-scale tool kit, he’s in.