Researchers Can Control Cellular Behavior through Artificial Organelles

Wednesday, August 5, 2020 - 11:00
Artificial Organelles

Duke University biomedical engineers have demonstrated a method for controlling the phase separation of an emerging class of proteins to create artificial membrane-less organelles within human cells.

According to the paper published in the journal Nature Chemistry on August 3, proteins function by folding into specific 3-D shapes that interact with different biomolecular structures, phys.org reports.

Researchers previously believed that proteins needed these fixed shapes to function. But in the last two decades, a large new class of intrinsically disordered proteins (IDPs) have been discovered that have large regions that are "floppy"—that is, they do not fold into a defined 3-D shape. It is now understood these regions play an important, previously unrecognized role in controlling various cellular functions.

IDPs are also useful for biomedical applications because they can undergo phase transitions—changing from a liquid to a gel, for example, or from a soluble to an insoluble state, and back again—in response to environmental triggers, like changes in temperature. These features also dictate their phase behavior in cellular environments and are controlled by adjusting characteristics of the IDPs such as their molecular weight or the sequence in which the amino acids are linked together.

"Although there are many natural IDPs that show phase behavior in cells, they come in many different flavors, and it has been difficult to discern the rules that govern this behavior," said Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke. "This paper provides very simple engineering principles to program this behavior within a cell."

This simpler version allowed the researchers to make precise changes to the molecular weight of the IDP and amino acids of the IDPs. The researchers show that, depending on how these two variables are tweaked, the IDPs come together to form these compartments at different temperatures in a test tube. And by consistently trying various tweaks and temperatures, the researchers gained a solid understanding of which design parameters are most important to control the IDP's behavior.

"This is the first time anybody has been able to precisely define how the protein sequence controls phase separation behavior inside cells," said Dzuricky, Michael Dzuricky, a research scientist working in the Chilkoti laboratory and first author of the study.

"We used an artificial system, but we think that the same rules apply to natural IDPs and are excited to begin testing this theory."

"We can also now start to program this type of phase behavior with any protein in a cell by fusing them to these artificial IDPs," said Chilkoti. "We hope that these artificial IDPs will provide new tool for synthetic biology to control cell behavior."

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