Unveiling the Shapeshifting Mechanisms of Metamorphic Proteins

Metamorphic proteins—often called the "shapeshifters" of bacterial, animal, and human cells—possess a unique ability to transition rapidly between two distinct shapes. This adaptability allows them to perform various functions and respond to changing environmental conditions.

Despite their biological significance, the mechanisms behind these shape changes remain poorly understood. A new study published in the Proceedings of the National Academy of Sciences (PNAS) proposes a bold theory to help unravel this mystery, according to co-author John Orban, a professor in the Department of Chemistry and Biochemistry at the University of Maryland and the Institute for Bioscience and Biotechnology Research (IBBR).

Orban and his co-author, Andy LiWang, a professor of Chemistry and Biochemistry at the University of California, Merced, suggest that many metamorphic proteins exhibit an "underlying temperature dependence." If confirmed, this would indicate that temperature—particularly cold temperatures—plays a crucial role in triggering these proteins' shape changes.

A deeper understanding of metamorphic proteins could significantly impact biomedical research and the development of life-saving treatments. "It may be possible to design proteins that are switchable and have more than one function," Orban explains. "For example, they could serve as stealth proteins that enter a cancer cell in one state but switch under certain conditions to a form that can kill the cell."

While it is well established that metamorphic proteins respond to various environmental triggers such as oxidation and changes in acidity, Orban and LiWang's theory goes further. Their research seeks to explain why metamorphic proteins maintain a balance between different forms.

"Metamorphic proteins cannot shapeshift unless there is an equilibrium between the two states, and our hypothesis is that temperature is the underlying factor maintaining this balance. We believe this may be a universal mechanism," Orban says.

The foundation for this theory was laid by a 2023 study co-authored by Orban. That study found that an engineered metamorphic protein alternated between folded states when scientists varied the temperature within a narrow range of 5 to 30°C.

"There are now some naturally occurring metamorphic proteins known to do this, but ours was the first designed protein that switches reversibly using only temperature. Andy and I started discussing whether other metamorphic proteins follow the same pattern," Orban recalls.

In their latest study, published in PNAS, Orban and LiWang examined 26 pairs of previously studied metamorphic proteins through the lens of their temperature dependence hypothesis. They focused on differences in hydrophobic contacts—water-repelling regions that help stabilize protein structures.

The researchers found that nearly all protein pairs showed significant differences in hydrophobic contacts where experimental data was available. These variations correlated strongly with temperature-dependent changes. In particular, proteins in lower-temperature states exhibited fewer hydrophobic contacts, making them more flexible and facilitating their ability to shapeshift.

"It is a working hypothesis, but so far, the evidence supports it," Orban says. "We were surprised because we thought this was a pretty bold idea."

This research could pave the way for identifying more metamorphic proteins, which remain elusive. Currently, fewer than 100 metamorphic proteins are known, compared to approximately 200,000 monomorphic proteins—those with a single stable structure—cataloged in the global Protein Data Bank. Orban believes some proteins currently classified as monomorphic may, in fact, be metamorphic, shifting shapes when exposed to temperature changes.

While Orban's primary focus is on understanding the fundamental mechanisms behind these proteins, he remains optimistic about their potential applications.

"Our interest has been mostly fundamental so far, but we are considering possible biotechnology applications. And I don't think it's just wishful thinking. In the not-too-distant future, we may be able to predict, design, and put metamorphic proteins to work in meaningful ways," he concludes.