Scientist Collaborates to Investigate Protein Shape Shifting

man working in a lab

Tyler Gonzalez, a UW graduate student in molecular biology from Bradenton, Fla., works in Thomas Boothby’s laboratory on a machine that uses fluorescence to determine the intactness of sample proteins. Boothby, an assistant professor in the UW Department of Molecular Biology, is part of a $992,485 National Science Foundation three-tier study that will examine how a special class of proteins changes shape and how the changes help an organism survive extremely dry conditions. (UW Photo)

University of Wyoming researchers, in collaboration with others across the U.S., will begin investigating how environments can turn proteins into jack-of-all-trades journeymen.

Molecular biologist Thomas Boothby’s laboratory is part of a $992,485 National Science Foundation three-tier study that will examine how a special class of proteins changes shape and how the changes help an organism survive extremely dry conditions. The project title is “Functional Synergy Between Disordered Proteins and their Environment in Desiccation Protection.”

Researchers want to understand how the chemical environment in which disordered proteins are immersed — in this case, extreme dryness — dictates their shapes and functions.

“So, by changing their environment, you can change how these proteins are working,” says Boothby, an assistant professor of molecular biology, whose laboratory studies how organisms can survive extreme environments.

Boothby then wants to apply what is learned to stabilize biomedical materials, such as blood, and to produce hardier crop plants. Disordered proteins are dispersed throughout the kingdoms of life. Most proteins have a stable three-dimensional structure. They are like little machines: Their structure helps them do their jobs, Boothby says.

“These disordered proteins lack a stable three-dimensional structure, and they are constantly changing their shape,” he says. “They seem, to us, like they should be constantly breaking but, in fact, they serve vital roles.”

Other members of the research group are Alex Holehouse, an assistant professor of biochemistry and molecular biophysics at Washington University in St. Louis; and Shahar Sukenik, an assistant professor of chemistry at the University of California-Merced.

Holehouse, one of the world’s leading experts in the understanding of and in computer modeling the disordered proteins, will predict what function comes from changing a protein’s shape, while Sukenik will measure the changes. Boothby’s laboratory then will test what those changes in shapes really do for the organism that’s drying out and how they help that organism survive.

For example, as a pond dries up, an organism starts drying out, and the chemical environment inside itself is going to change as a lot of water is lost. In response, the disordered proteins are probably going to change shape slightly to take on different functions, he says.

“We’ve found there are disordered proteins that help these organisms survive,” Boothby says. “As the chemical environment inside the cells is changing, these disordered proteins that help them survive that stress are probably being induced to take on that protective function by that change.”

Boothby suggests thinking of proteins like cogs in a machine. If the cog suddenly turned into a square, it’s not going to fit into the machine to do its job. But, in many cases, the disordered proteins may fit in perfectly with other protein machinery around them.

Scientists have thought a protein might break if changing shape.

“What we’re finding is that it actually allows them to take on multiple roles and interact with many different proteins,” he says. “By being flexible instead of breaking, it just gives more versatility to these molecules.”

Boothby’s lab focuses on how tardigrades can survive being completely dried out; being frozen to just above absolute zero (about minus 458 degrees Fahrenheit, when all molecular motion stops); heated to more than 300 degrees Fahrenheit; irradiated several thousand times beyond what a human could withstand; and even survive the vacuum of outer space.

“This is one thing we’ve been actively pursuing with our tardigrade proteins is how can we change the sequence of the protein to make it function in a certain way,” he says. “For example, we want to make them better at preserving human blood. We make small tweaks to the protein sequence, it changes the shape slightly, and it makes the protein either work better or worse for that application.”

Scientists not only will be able to change the sequence, but also change the proteins’ environment.

“We know what sort of solution we put these proteins in has a big influence on how they function,” he says. “This gives us another tool to get these proteins to do what we want.”

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