Thursday, September 28, 2023

A new source of cellular order in the chemistry of life

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Perhaps the question isn’t why aggregates form in disease, but why they don’t form in healthy cells. “One of the things I often ask in group meetings is, why isn’t the cell scrambled eggs?” Hyman said in his speech at the cell biology meeting; the protein content of the cytoplasm is “so concentrated that it should just escape from solution”.

Two types of proteins (red, yellow) isolated from the nucleoli of frog eggs can spontaneously organize into droplets of condensate. By changing the concentrations of each protein in the solution, researchers can make one or both types of condensate grow or disappear.Courtesy of Marina Feric & Clifford Brangwynne

A clue came when researchers in Hyman’s lab added ATP cellular fuel to purified stress pellet protein condensates and saw those condensates disappear. To further their research, the researchers put egg whites in test tubes, added ATP to one tube and salt in the other, and then heated them. While the egg whites in salt aggregated, those containing ATP did not: ATP prevented protein aggregation at the concentrations found in living cells.

But how? It remained a puzzle until Hyman ran into a chemist while delivering a seminar in Bangalore. The chemist noted that in industrial processes, additives called hydrotropes are used to increase the solubility of hydrophobic molecules. Back in his lab, Hyman and his colleagues discovered that ATP worked exceptionally well as a hydrotrope.

Surprisingly, ATP is a very abundant metabolite in cells, with a typical concentration of 3-5 millimolar. Most enzymes that use ATP work efficiently at concentrations three orders of magnitude lower. Why, then, is ATP so concentrated inside cells, if it is not necessary to trigger metabolic reactions?

One possible explanation, suggests Hyman, is that ATP does not act as a hydrotrope below 3 to 5 millimolar. “One possibility is that at the origin of life ATP evolved as a biological hydrotrope to maintain soluble biomolecules at high concentration and was then co-opted as energy,” he said.

It’s difficult to test this hypothesis experimentally, Hyman admits, because it’s difficult to manipulate the hydrotropic properties of ATP without also affecting its energy function. But if the idea is correct, it could help explain why protein aggregates are commonly formed in diseases associated with aging, because ATP production becomes less efficient with age.

Other uses of droplets

Protein aggregates are clearly bad in neurodegenerative diseases. But the transition from the liquid phase to the solid phase may be adaptive in other circumstances.

Take primordial oocytes, cells in the ovaries that can lie dormant for decades before they become an egg. Each of these cells has a Balbiani body, a large condensate of amyloid protein found in the oocytes of organisms ranging from spiders to humans. It is believed that the Balbiani body protects the mitochondria during the dormant phase of the oocyte by group the majority of mitochondria together with long fibers of amyloid protein. When the oocyte begins to mature into an egg, these amyloid fibers dissolve and the Balbiani body disappears, explains Elvan Böke, cell and developmental biologist at the Barcelona Genomic Regulation Center. Böke is working to understand how these amyloid fibers assemble and dissolve, which could lead to new strategies for treating infertility or neurodegenerative diseases.

Protein aggregates can also solve problems that require very rapid physiological responses, such as stopping bleeding after injury. For example, Mucor circinelloides is a fungal species with interconnected and pressurized networks of root hyphae through which nutrients circulate. Researchers at the Temasek Life Sciences Lab led by evolutionary cell biologist Greg Jedd recently discovered that when they hurt the end of a Mucor hyphae, the protoplasm sprang up at first but almost instantly formed a gelatinous plug which stopped the bleeding.

Jedd suspected that this response was mediated by a long polymer, possibly a protein with a repeating structure. The researchers identified two candidate proteins and found that, without them, the injured fungi would bleed catastrophically in a puddle of protoplasm.


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