Discoveries in protein organization could lead to new CF treatments
CFTR interaction with proteins, other molecules may contribute to CF: Study
Discoveries into the process underlying protein organization on cell membranes could ultimately lead to new ways to treat cystic fibrosis (CF), according to a study from Canada that shed light on some of the mechanisms underlying the disease.
The study found that proteins linked to CF organize themselves into clusters on these membranes through a process known as phase separation. This mechanism enables proteins to essentially form hubs that help control the flow of salt and water in and out of cells.
When this clustering is disrupted — as it is in people with CF — the imbalance contributes to the symptoms associated with the genetic disease, per the researchers. The team noted that these findings could open the door to potential new therapies.
“Therapeutics for cystic fibrosis have hit a plateau, demanding that we uncover new ways of looking at the science behind the condition,” Jonathon Ditlev, PhD, a professor at the University of Toronto and researcher at the Hospital for Sick Children (SickKids) in Canada, said a press release. “By studying protein organization, we’ve uncovered a brand-new avenue for developing therapeutics for cystic fibrosis.”
The study, “Protein interactions, calcium, phosphorylation, and cholesterol modulate CFTR cluster formation on membranes,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).
Protein interactions, organization in CF remains poorly understood
CF is caused by mutations in the CFTR gene, which result in missing or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein is normally present at the surface of certain cells where it acts like a gate that regulates the movement of water and salt molecules, particularly chloride ions, in and out of cells.
As a result, cells cannot regulate the flow of chloride and water and instead produce unusually thick and sticky mucus, which builds up and causes damage to certain organs, particularly the lungs.
Besides working as a chloride channel, CFTR also contributes to regulating ion homeostasis, particularly of sodium and calcium, which is thought to involve the formation of molecular hubs, or clusters, composed of CFTR and its binding partners. Homeostasis means maintaining conditions inside cells that contribute to their function.
In people with CF, these clusters are disrupted and may contribute to the disease.
According to the researchers, however, “while membrane lipids are known to play a role in cluster formation, the contribution of protein interactions is not well understood.” Lipids, or fatty molecules, are the main components of cell membranes.
Christine Bear, PhD, codirector of the Cystic Fibrosis Centre at SickKids, noted that “current therapies for cystic fibrosis are effective for most children, but not all.”
This work may help, per Bear, who already is working with the research team to advance these findings.
“These findings could help us target those for whom current therapies remain ineffective, while also bolstering outcomes for all those affected by CF,” Bear said.
Our findings establish CFTR as a phase-separating protein, opening up a previously unexplored mode of protein regulation and a new target for future therapies.
In this study, the researchers used a combination of laboratory assays and computational modeling to investigate how molecular interactions between CFTR and its binding partners, membrane cholesterol, a type of fat, and other molecules could induce cluster formation.
The team found that the process of CFTR cluster formation may involve multiple interactions between CFTR and other proteins, calcium, and membrane lipids, consistent with a process known as membrane-associated biological phase separation. In this process, clustered regions separate from the surrounding areas of the membrane, helping to organize distinct membrane compartments. This separation concentrates specific proteins and molecules within these clusters, enabling the cell to spatially regulate important functions such as ion transport and signaling.
Other mechanisms may also involve the phosphorylation of domains of the CFTR protein located inside cells in the absence of calcium. Phosphorylation is the addition of a phosphate group to specific parts of a protein, a modification that can influence the protein’s function, interactions, or positioning within the cell.
Julie D. Forman-Kay, PhD, colead author of the study, had proposed, back in 2017, that phase separation might be relevant to CFTR, per the release.
Now, “our findings establish CFTR as a phase-separating protein, opening up a previously unexplored mode of protein regulation and a new target for future therapies,” Forman-Kay said.
About the Author
