Saturday, June 10, 2023

How might chimeric, droplet-forming proteins contribute to cancer?

A review article sheds light on the latest science in this area, focusing on protein droplets, known as “ectopic condensates.”

Buffalo, NY — In the predisposition to cancer, genetic mutations can sometimes lead to the formation of chimeric proteins made up of parts of two different proteins that are usually different.

A new review paper examines the latest science on a certain class of “oncofusion proteins” associated with these cancers, focusing on those oncofusion proteins that can form liquid-like droplets called “ectopic condensates” in cells.

The article was published April 25 in Trends in Cell Biology by University at Buffalo researchers Richu B. Davis, Mahdi Muhammad Moosa, and Priya R. Banerjee in the Department of Physics in the UB College of Arts and Sciences. Banerjee, PhD, is an assistant professor of physics, and Davis, PhD, and Moses, PhD, are postdoctoral associates in the Banerjee lab.

In laboratory experiments, ectopic condensates form when part of a protein that normally forms droplets combines with part of another protein that is usually found at a different location within a cell. The resulting chimeric protein retains some functions from both the original proteins, and is able to form droplets in the “wrong” place inside cells, Moses says.

The researchers say that protein droplets, also known as “membrane-less organelles,” can serve as centers of biochemical activity, so it’s interesting to investigate misplaced droplets with unusual functions.

“An important audience for our review is cancer researchers,” Moses says. “Biophysicists studying biomolecular condensates may already be familiar with these concepts, but we wanted to share these insights with cancer biology researchers who are working directly with patient samples.”

Davis notes that ectopic condensates may provide an attractive target for cancer therapeutics, but more research is needed to better understand how these chimeric proteins function in their natural state and how they regulate gene transcription. How can we recapitulate what leads to cancer development: “The cell is a very complex system,” he says. “We need better tools to study protein condensates in their native conditions, and Our future studies will be focused on addressing this.”

In the review article, the authors summarize emerging findings from several recently published work from different research groups, including a 2021 study recently completed with UB Physics PhD graduate Taranpreet Kaur.

That earlier paper, “On the Biophysics of Biomolecular Condensates” appearing in a special issue of the journal Protein Science, focused on oncofusion proteins of a FET family and was titled, “FUS oncofusion protein condensates mSWI/SNF”. Chromatin recruits the remodeler through heterotypic interactions between prion-like domains.” The team showed how these ectopic protein condensates can recruit key molecular machines to alter the balance of gene regulation.

“The discovery of protein phase separation has changed our view of how cells organize their internal space,” says Banerjee. “As more and more research is emerging in this exciting field, we are learning about the role of protein droplets in key biological processes such as gene regulation and their role in fatal human diseases. Based on emerging data from various laboratories, We suspect that a subset of cancer-associated fusion proteins may form a new type of condensate, which normal cells do not possess.

“Studying naturally occurring fusion proteins with new biological functions and their condensation is important not only from the perspective of cancer biology but also from the perspective of protein engineering, because learning how these fusion proteins work can lead to novel opportunities for novel fusion proteins.” There will be new opportunities for making artificial proteins with applications in biomedical sciences,” says Banerjee.

Research in the Banerjee lab is supported by grant awards from the National Institute of General Medical Sciences, the National Institute on Aging, and the National Center for Advancing Translational Sciences, all part of the National Institutes of Health, along with the My Stone Good Trust and UB. College of Arts and Sciences.

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