The Purpose-Driven Cell

Solution nuclear magnetic resonance [NMR] measurements
Solution nuclear magnetic resonance [NMR] measurements show that peptides (green spheres, left) or small molecule ligands (purple spheres, right) bind to adjacent regions of the PAS kinase PAS-A domain, suggesting possible regulatory interactions between these events. (Credit: Roksana Azad)
Researchers find clues to how the PASK protein impacts cell differentiation.

Per-Arnt-Sim (PAS) protein domains are found across all kingdoms of life, from prokaryotes to humans. PAS domains are involved in sensing and integrating metabolic and external signals, which helps cells respond to changes in their environment. Despite the ubiquity of PAS domains, how many of them function is still not fully understood. A new study published in the Journal of Molecular Biology reports how researchers have used new technologies to determine how an interaction within a specific PAS domain leads to cell growth and differentiation in mammals.

“PAS domains often serve as the eyes, nose, and taste buds of the cell,” said Kevin Gardner, founding director of the Structural Biology Initiative at the CUNY ASRC and co-corresponding author of the study. “It’s how cells sense what’s going on in the environment around them. Based on the information they sense, the cell then says, ‘go turn some genes on, grow in this direction, change your metabolism,’ you name it.”

The new study builds upon 25 years of research into the underlying mechanisms involved in how a specific PAS domain called PAS Kinase (PASK) controls the fate of stem cells in mammals. Metabolic signals turn PASK on and off — in part by controlling whether this enzyme is outside or within the nucleus — to determine whether the cell differentiates and divides.

Previous research has found glutamine to be an important nutrient in controlling where PASK resides in the cell. When glutamine is low, PASK stays in the main part of the cell, which keeps the stem cell from dividing. When glutamine is high, PASK moves into the cell nucleus, where the genetic information is stored, and causes the cell to start dividing and specializing.

PASK itself is made of multiple components, including PAS-A, which has been experimentally verified, and PAS-B, which is a predicted component Their functions have been explored over the years, and Gardner likens this research to being an archeologist trying to determine the functions of different parts of an unfamiliar structure.

“We’re structural biologists, so we believe that by understanding atomic structures of proteins — the machinery of the cell — we can figure out a bit about how they work,” Gardner said. “Our job is similar to an archaeologist digging up a car 1,000 years from now and trying to figure out how the engine works. We see where different pieces and parts of the proteins are, and then what we do is we start throwing other molecules at it to see if any of those bind and change the structure.”

In this study, the researchers found that an interaction between PAS-A and another part of the protein, PIM (for “PAS Interacting Motif”), controls whether PASK moves into the nucleus. PAS-A contains a nuclear localization sequence that normally would direct PASK to move into the nucleus. But when PIM binds to PAS-A, it hides this signal, keeping PASK where it is. This interaction was found to be influenced by a cell’s metabolic state, explaining at least one reason why glutamine had a similar influence in the previous study.

Since PASK’s movement into the nucleus is crucial for the process of stem cell differentiation, the study’s findings are particularly important. The researchers suggest that manipulating the interaction between PAS-A and PIM could be a potential strategy for controlling stem cell fate, which could have implications for developing therapies for various diseases. Furthermore, understanding these protein interactions could lead to further discoveries about how PASK, and more broadly other PAS-containing domains, are regulated in cells.

“We still want to identify what the exact metabolic signal is, whatever that small molecule is that can turn this on and off,” said Gardner. “If we understand that better, it’s a critical link into the biology of disease. If the levels of that unknown molecule are too high or low, it is likely impacting the signaling here in ways we want to be able to control in the future.