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Assemblages: 50 Years Later, We Know Nothing About Them

cell bio

You would think we learn about every part of a cell in biology, but we really don’t. Case in point, about 50 years ago, electron microscopy revealed the presence of tiny blob-like structures that form inside cells, move around and disappear. The reason you probably haven’t heard of these structures is because scientists really don’t know what they do even 50 years later. Although they do have an idea about them, these shifting cloud-like collections of proteins are believed to be crucial to the life of a cell, and will ideally offer a new approach to disease treatment.

Now two researchers are issuing a call to investigators from various backgrounds, from biophysics to cell biology, to focus their attention on the role of these formations— for which they even coin a new unifying term “assemblages.”

“I want to know what these assemblages are doing in Ewing sarcoma, the disease I concentrate on—and I would think all other researchers who study human biology would want to know their functions in both health and disease,” says Jeffrey Toretsky, MD, professor in the department of oncology and pediatrics at Georgetown Lombardi Comprehensive Cancer Center.

So Toretsky got himself a partner, co-author Peter Wright, PhD, to pull together all the biophysics and protein biochemistry knowledge available on assemblages into a review article. Toretsky also called on the expertise of chemists and physicists from Georgetown University to help solve this mystery.

Photo credit: The paper cited below. Assemblage formation leads to emergent properties of protein and RNA binding. This series of panels (A–D) demonstrates that an increase in the local concentration of protein (yellow ribbons) in regions of a cell can result in a phase transition (yellow haze) to form an assemblage once a critical concentration has been reached. A phase separated assemblage can be formed through weak homotypic or heterotypic interactions and allows exchange of constituent molecules with the surrounding solution. This phase-separated material allows for the capture and interaction of other protein or RNA species (cyan molecule). (D) The final assemblage formation shows the sequestration of two RNA molecules.

Photo credit and caption: The paper cited below. Assemblage formation leads to emergent properties of protein and RNA binding. This series of panels (A–D) demonstrates that an increase in the local concentration of protein (yellow ribbons) in regions of a cell can result in a phase transition (yellow haze) to form an assemblage once a critical concentration has been reached. A phase separated assemblage can be formed through weak homotypic or heterotypic interactions and allows exchange of constituent molecules with the surrounding solution. This phase-separated material allows for the capture and interaction of other protein or RNA species (cyan molecule). (D) The final assemblage formation shows the sequestration of two RNA molecules.

The team notes that these assemblages are often (but not always) made up of proteins that are intrinsically disordered. This means that they do not assume a specific shape in order to fit like a lock and key onto other proteins. These intrinsically disordered proteins seem to find each other and then form into gel-like assemblages — in a process called “phase separation” — that can trap and interact with other proteins and even RNA. These are the biological molecules that help decode and regulate genes, so these assemblages must have an impact on what the cell is doing.

To add to their mystery, when their work is done—whatever that is—the assemblages dissolve.

“It is only in the last five years that researchers have begun recognizing that proteins without fixed structures may have important transitional properties that change based upon their local abundance in cells,” Toretsky says.

The two researchers suspect that if these assemblages play a role in disease, they could be targeted with a small molecule.

“Current drug-discovery dogma suggests that it is very hard to make a small molecule to prevent two structured proteins from interacting. However, small molecules have a greater likelihood of disrupting intrinsically disordered protein-protein interactions,” says Toretsky.

“This review links together very basic biologic phenomena of protein interaction with the potential for new drug discovery,” he says. “It’s an exciting challenge.”

We still don’t know exactly what they do, but the thrill of the discovery and possible implications, is huge. It seems no matter how much we know about the body, there is always much, much more we can learn. It’s much more exciting knowing we don’t know everything anyway.

Want more? You can find the full (yes full!) call to arms so to speak —here!

Sources
Toretsky, J., & Wright, P. (2014). Assemblages: Functional units formed by cellular phase separation The Journal of Cell Biology, 206 (5), 579-588 DOI: 10.1083/jcb.201404124

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