Blobs. Clouds. Assemblages. All these terms have been applied to poorly defined protein clusters that mysteriously form inside cells and then just as mysteriously disappear. These protein collections might be considered fuzzy outliers. After all, they defy the usual expectations for proteins. Proteins are supposed to assume definite structures that confer highly specific activities. Proteins—we like to think—work with each other and their nonprotein partners in lock-and-key fashion.

Inviting the scientific community to think about proteins—or rather protein assemblages—in new ways, researchers at Georgetown University and The Scripps Research Institute (TSRI) have formed an assemblage of their own: a review article that gathers together all the biophysics and protein biochemistry knowledge available on protein “blobs,” “clouds,” or the like.

The review appeared September 1 in the Journal of Cell Biology, in an article entitled, “Assemblages: Functional units formed by cellular phase separation.”

“The partitioning of intracellular space beyond membrane-bound organelles can be achieved with collections of proteins that are multivalent or contain low-complexity, intrinsically disordered regions,” wrote the authors. “These proteins can undergo a physical phase change to form functional granules or other entities within the cytoplasm or nucleoplasm that collectively we term ‘assemblage.’”

The authors—Georgetown’s Jeffrey Toretsky, M.D., and TSRI’s Peter Wright, Ph.D.—say that these assemblages are often, but not always, composed of proteins that apparently prefer not to assume specific shapes. Yet these proteins—called intrinsically disordered proteins—seem to find each other, forming gel-like assemblages in a process known as phase separation. When their work is done—whatever it is—the assemblages dissolve, noted Dr. Toretsky.

“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,” Dr. Toretsky added.

Dr. Toretsky suspects 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.”

This breadth of interest—from basic biology to drug development—is reflected in the review, which not only notes that assemblages appear to be involved in disease states, but also states that intrinsic disorder and phase transitions should be considered in the development of therapeutics.

“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,” Dr. Toretsky remarked.

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