Yeast proteins reveal the secrets of drought resistance

Our bodies are made up mostly of water. If this water is removed, our cells cannot survive, even when water is reintroduced. But some organisms can completely dry out yet return to life when rehydrated.

A new study in Cell Systems helps explain how organisms can come back from desiccation (the removal of water or moisture) while others fail by looking at the cell’s proteins. In the first survey of its kind, a team of researchers profiled thousands of proteins at once for their ability to survive dehydration and rehydration.

“We are figuring out the rules of what makes a protein tolerant or intolerant to extreme water stress, also known as desiccation,” says Shahar Sukenik, lead author and assistant professor in the Department of Chemistry at Syracuse University. His lab led the study in close collaboration with labs led by co-corresponding authors Stephen D. Fried of Johns Hopkins and Alex Holehouse of Washington University School of Medicine in St. Louis, and with labs at University of Wyoming and University of Utah.

Some proteins appear innately more tolerant to water loss, while others are more fragile, the researchers found. The team used yeast as their model system. The team used mass spectrometry to profile how proteins withstand drying and rehydration. They also deployed AI-driven tools to identify the shapes, chemistries and features of these proteins, revealing the rules of their dehydration tolerance.

“Most proteins will lose over three-quarters of their copies following a dehydration-rehydration cycle,” says Sukenik, “but some proteins do much better, with a large majority of their copies surviving the process.”

The proteins that survived water loss tended to be smaller, tightly folded, with fewer interactions and distinct surface chemistry. One key trait was a high number of negative charges on the surface of tolerant proteins, which seems to protect them during drying and after rehydration.

The team then used these chemical rules to increase the dehydration tolerance of a protein. They focused on the Green Fluorescent Protein—GFP—which in its original form is not tolerant to dehydration. By introducing targeted mutations, the researchers managed to increase the dehydration tolerance of GFP such that nearly 100% of the proteins remained active following rehydration. The team is currently applying this strategy to design novel, dehydration resistant proteins.

Protecting producer proteins

The study also revealed a pattern in the function of proteins that survived and those that did not.

“The most tolerant proteins not only have a specific surface chemistry, but also happen to have very specific functions,” says Sukenik.

Resilient proteins were typically ones that are responsible for creating small molecules, the essential building blocks of the cells.

“Everything starts from these small building blocks, which are then used to create larger biomolecules, including other proteins,” says Sukenik. “If the cell runs out of these small building blocks for whatever reason, that’s it. The cell is stuck. It’s like a car running out of gas.”

Dehydration sensitive proteins, by contrast, were typically involved in energy-costly jobs, such as making ribosomes, which are the cell’s protein factories.

Yeast cells appear to gain an evolutionary advantage during dehydration by protecting the proteins that produce their building blocks. At the same time, they get rid of the proteins that consume these building blocks at a rapid pace. This differentiation allows yeast cells to slowly return to an optimal resource balance when water returns.

“We think these ‘producer’ proteins have evolved to develop the specific chemistry that allows them to rehydrate, so when water hits the dehydrated cell they kick into action and enrich the environment with the building blocks they produce,” Sukenik says.

Language of survival

This work could reframe current thinking about biological survival strategies. Dehydration tolerance may not be limited to a few hardy species. Instead, this ability could reflect an underlying “grammar” written into the chemistry of proteins, the researchers note. By revealing that grammar, the team is not only explaining how life adapts to stress, but also using those strategies towards novel protein design.

The researchers envision potential applications in biotechnology, such as engineering proteins for longer shelf life in therapeutics and food. Protein-based medicines—such as insulin or antibodies—could be stored and transported without refrigeration, significantly extending their shelf life and making them easier to distribute, especially in areas where cold storage is difficult. This approach could make protein therapeutics more accessible and reliable.

“During the COVID-19 pandemic, there were problems in cold chain delivery which hindered access to vaccines,” says Sukenik. “But when your product is dehydrated, you won’t have to keep it cold. The shelf life of medicines, food, or other protein-based products could be extended by months or even years.”

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