Hometown U: Researching how cells traffic in copper

Kathleen McCoy

As college students streamed back to UAA last week, buying books and parking permits, figuring out class schedules and lab fees, Jason Burkhead, an assistant professor in biological sciences, was retooling his biochemistry lab for a fresh scientific inquiry.

Specifically, he wants to know how a particular “traffic cop” protein in human liver cells decides to manage the pump that controls copper levels within the cell.

The traffic cop has three choices: Store the pump in a part of the cell that supplies copper for essential proteins, send the pump toward the outer cell membrane to get rid of excess copper or recycle and degrade what isn’t needed.

Copper is an important trace element for just about everything alive, from humans to plants to microorganisms. It ensures that metabolic processes like nutrient absorption or iron mobilization happen. We can’t survive without it, yet too much of it is toxic. So precisely how a cell manages copper levels is very important. 

Burkhead isn’t the only one who wants to understand it. The National Science Foundation awarded his lab a three-year, $395,000 grant to approach the answer.

He’s starting with something called “com-D1,” which is written as COMMD1, the protein that makes all those trafficking decisions about the copper pump.

“The NSF is interested in how this works, but more broadly they’d like us to build some predictive models for how cells make these trafficking decisions, not just about copper pumps, but about other proteins as well. So if we enrich for some of these traffic signals, if they are activated, do we expect an increase in traffic in one direction? Can we start to predict that?”

To find out, Burkhead will be studying trafficking processes in live cells. “We’ll grow cells in culture, and then we’ll treat them with copper. Or we’ll limit the copper, or change the COMMD1 level.”

This work will be useful in a number of areas that Burkhead is already working in.

A healthy liver processes what we eat and drink into energy and nutrients the body can use. On another project, Burkhead is investigating non-alcoholic liver disease, common among about 30 percent of the U.S. population. It tends to develop in those who are overweight or obese, or have diabetes, high cholesterol or high triglycerides. The disease occurs when the liver has trouble breaking down lipids and fats, causing them to build up in the organ. It may be caused by copper deficiency; too little copper affects the way the liver can metabolize those lipids.

Conversely, a rare inherited disorder called Wilson disease indicates excessive levels of copper in the liver, brain and eyes. A specific protein, called the Wilson disease protein, is responsible for transporting copper out of a cell; again, it gets some of its directions from COMMD1, the focus of Burkhead’s newest research.

An element of the NSF grant is creating research opportunities for undergraduates who can support the work by culturing liver cells, doing some standard molecular biology and helping to develop the computational models that might predict the structure of COMMD1 and how it influences trafficking within cells.

“At this point, we can’t fully trust any computational model of a protein until we validate it,” Burkhead said. “But when I get undergrads involved in that part, it helps them think about how proteins are put together and how they work. We can run some predictive models, and then take a bunch of those and ask, ‘Which don’t look like they make sense? Which might have problems?’ We can go back and forth between predictive models and protein chemistry in the lab.”

Discovery experiences like these are how research scientists influence academic curriculum. Burkhead’s students don’t work with a textbook; he has them reading freshly published science journal articles and working with primary source material. They’re delving in an area filled with questions; they may get a glimpse at some answers.

Although he’s essentially a biochemist, Burkhead came to his current interest by figuring out how plants handle copper. His doctorate is in botany from Colorado State University, though it wasn’t the plants but the copper-handling machinery in plants that grabbed his interest.

“I started out as an ecology student, but then I wanted to do something more reductionist,” he said. So he found work in a Colorado lab doing phytoremediation -- using plants to clean up environmental contaminants. “We were genetically modifying plants to see where their limitations were, and if we could make something that worked better.”

His lab adviser had done work on protein trafficking to chloroplasts in plants, where photosynthesis happens. Burkhead worked alongside, taking plant cells apart to look at chloroplasts, and then taking apart chloroplasts. He’s essentially doing the same thing now, only with human cells. 

“There’s a million things we don’t know about cells,” Burkhead said. “This is just a tiny piece of that."

Kathleen McCoy works at the University of Alaska Anchorage, where she highlights campus life through social and online media.