Adenosine triphosphate (ATP) is widely considered biology’s “energy currency”. A crucial player in cell function, it stores and releases energy for enzymatic reactions in its phosphate bonds. But cells typically hoard amounts of ATP several hundred-fold higher than that needed by enzymes. A recent study published in Science offers a reason why: At the concentrations found in cells, ATP helps solubilize proteins and prevents them from clumping together, a state that can hinder protein function or create lesions that contribute to the onset of diseases such as Alzheimer’s.

The study, led by Yamuna Krishnan of the University of Chicago and Anthony Hyman of the Max Planck Institute of Molecular Cell Biology and Genetics, suggests that ATP’s molecular make-up helps proteins dissolve. ATP is highly water soluble itself, and contains charged phosphate groups that attract water, as well as an aromatic adenosine structure that’s drawn to large proteins’ water-resisting groups. As a result, molecules of ATP can surround proteins to form a dynamic, charged coat that makes them soluble in water, Krishnan explains.

The researchers stumbled across this potential role during in vitro studies of intracellular compartments formed by an RNA-binding protein named FUS (fused in sarcoma), the gene for which has been associated with Amyotrophic lateral sclerosis (ALS). They found that adding ATP to the solution dissolved these structures. “It started as a freak observation when trying to replicate the environment within a cell,” Krishnan says. “FUS usually forms very nice droplets, but they don’t form when ATP is added at physiological concentrations.”

To understand why, the team added ATP and magnesium ions when reconstituting FUS. At concentrations similar to what’s found in cells, pre-existing FUS compartments dissolved and new ones didn’t form. They saw similar effects on other proteins that form liquid compartments within cells. ATP also prevented the aggregation of proteins that tend to form amyloid clusters, the pathological clumps seen in neurodegenerative diseases such as Alzheimer’s. Other nucleotides including GTP, ADP, and AMP had similar effects, but they occur in much smaller amounts in cells.

The results demonstrate that ATP can keep unstructured proteins—the kind that tend to form pathological clusters—soluble within cells. “When you look at the structure of ATP, it’s obvious that it could have this action as a hydrotrope,” Krishnan says. “The real surprise was to see the concentration range at which this action occurs—it matches so well with the physiological concentration of ATP in cells.”

The work is a step toward understanding why cells have 8-10 millimolar concentrations of ATP when enzymes only need much smaller micromolar amounts to work. “I think we finally have at least one reason why this happens,” Krishnan adds.

Whether this mechanism is at play in vivo—and whether the solubilized proteins continue to function—will need further experiments. In future work, the researchers also plan to assess other cellular hydrotropes, and test whether age-related declines in cellular ATP levels may be linked to protein clumps in neurodegenerative disease.

“It’s pretty exciting that this accessory molecule can keep the high concentrations of proteins packed into cells soluble,” says biochemist Gregory Weiss of the University of California Irvine, who was not involved in the study. “This new role for ATP could open frontiers for understanding how molecules work inside cells.”

ATP’s protein-solubilizing role may be even more ancient than its energy storage functions, Krishnan says. Large molecules clumping together would have posed an early problem during the evolution of life, so it’s possible that ATP—as one of the basic building blocks of DNA and RNA—may have been deployed to solubilize proteins.

“This sort of turns ATP on its head, the idea that ATP evolved to solubilize proteins and only later to function as an energy source,” Weiss says. “One of the first examples of chemical energy we learn as kids is ATP, and it’s exciting to think we might have to re-teach that role.”