Has the Answer to Why Protein Clumping Doesn’t Poison Cells Been Hiding in Plain Sight?

To check, scientists boiled eggs.

When proteins in cells don't fold properly, they form clumps that cause multiple diseases. Could ATP be fixing the mess? Representative image. Credit: the3cats/pixabay

When proteins in cells don’t fold properly, they form clumps that cause multiple diseases. Could ATP be fixing the mess? Representative image. Credit: the3cats/pixabay

High-school textbooks introduced us to the biological cell as a small, wet enclosure with multiple compartments within, all of them properly demarcated by boundaries. While some of this is true, it’s too simple a picture overall. What the cell actually resembles is a test tube with millions of molecules crowded in it, some encased in well-defined globules and some floating in a soup called the cytoplasm. The question then arises: how does the cell manage to function in this chaos? How does it not become diseased?

Among the more abundant big-molecules within a cell are proteins. These molecules are like strings made of water-attracting (hydrophilic) and water-repelling portions (hydrophobic). When proteins fold, the water-repellent parts become buried close to the centre while the exposed fragments have an affinity for water, making the protein soluble. While the genetic material (DNA) has a special compartment, called the nucleus, to hide in, proteins cramp themselves everywhere inside the cell – especially in the cytoplasm.

The estimated protein concentration within the cytoplasm might be up to 100 mg/ml. Such a high concentration induces a risk of protein molecules forming clumps. When a protein does not fold properly due to genetic defects, the hydrophobic residues become exposed to water. A large number of such misfolded or open protein molecules tend to form aggregates. These aggregates serve as physical barriers within the cell and are toxic: by causing proteins essential for other processes to clump. Such cellular toxicity can manifest as multiple diseases. One example is neurodegeneration, where neurons die due to protein aggregation. So, the cell must labour to prevent such mishaps.

One way it does this is akin to how we regularly remove stains from our clothes: using a detergent. Each detergent molecule has oil-engaging and water-attracting parts: one clings to the stains and the other, to the surrounding water. Similarly, the cell uses compounds called hydrotropes, which are structurally similar to detergents but which do not aggregate easily to form ordered clusters, to disperse such protein-rich granules or aggregates.

A study recently reported in the journal Science describes a new hydrotrope – at least new to us because we’ve known it all along for serving an altogether different function within the cell.

Our not-so-perfect biology textbooks rightly describe adenosine triphosphate (ATP) as the fuel that drives all the activities within a cell. However, the Science study found that the ATP concentration within cells is almost 1,000-times higher than that required for its role as an energy source. It must have been up to something else, and the authors figure that ATP may be involved in keeping proteins soluble and preventing them from clumping up.

Because of its molecular structure, ATP can shield the hydrophobic parts of misfolded proteins from the surrounding aqueous cytoplasm and allowing them to dissolve better. The researchers show that at such high concentrations, ATP prevents the formation of clumps and also clears preformed protein aggregates. Such aggregates are known to kill neurons in Alzheimer’s disease.

To test their idea, they boiled eggs. Heating the egg-white’s proteins destroys their structure and causes them to clump. In the presence of ATP, they noted that this aggregation was postponed by up to 30 minutes.

However, these experiments were performed in vitro (in an artificial system) that simulated physiological conditions. The ATP concentration used for most of the experiments (around 8 millimolar) is more than twice as high as the usual average ATP concentration in human cells.

Sunil Laxman, a cell biologist at the National Centre for Biological Sciences, Bengaluru, agreed. “Those really high levels of ATP will be attained only in some, rapidly proliferating cells – or a few other types of cells – and is unlikely to be reached in many cells,” he said.

Avinash Patel, a cell biologist at the Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, and one of the lead authors of the study, acknowledged Laxman’s concern and mentioned that there have been no studies reporting how much the ATP levels vary within different neurons. However, he added in an email, “Neurons are long-lived cells… Studies have shown there exist differences in ATP levels that span across the cell body, axons and synapses. Therefore, ATP levels locally can reach high concentrations (around 2 millimolar at synapses).”

He and his colleagues also speculate that declining ATP levels, perhaps as cells age or due to dysfunctional mitochondria, could increase the risk of neurodegeneration. However, Laxman said, “There are no real estimates of how much ATP drops (though there is definitely known, decreased mitochondrial function in aged cells/tissues), and if it really drops so much below the levels that the authors claim are present.

So this is what the authors intend to study in the future. Patel: “We are currently systematically measuring the ATP levels in different cells (particularly neurons) as we age them in culture and in different model organisms.”

This study also offers insights into a problem that has intrigued many scientists: how did cells evolve to their present elegant form? When life first formed on the planet, protein aggregation would have presented a significant problem for cells to deal with.

The scientists think that ATP could have come to the rescue – but have become co-opted over the course of evolution for its better-known function as an energy source.

For a molecule that was discovered 88 years ago, ATP continues to be studied in limited ways. And the Science study is the latest reason why we need to keep revisiting our fundamental biological units with fresh perspectives, to uncover all the feats they are capable of performing.

Neha C.V. is a masters student in molecular and cell biology at the Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru.

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