The cells in our bodies rely on proteins to carry out virtually all of the critical processes that underlie our health and physiology. They relay messages from one structure to another, they transport materials and help move cells; they aid in the operation of the immune system, the regulation of our metabolism, and the synthesis of new structures. In the past, scientists relied on long-standing assumptions about proteins, and those principles have guided them to many conclusions in the realm of protein biology. However, there are many mysteries that remain, especially surrounding one particular class of protein that has not fit well into the dogma that is usually applied. Now, work reported in the journal eLife has revealed new details about these proteins, research which could be instrumental in creating new disease treatments for everything from cancer to neurological illness.
We cannot know how long it might take for the discoveries about these so-called intrinsically disordered proteins to reach the clinic. But the Chair of the Johns Hopkins Department of Biology, Professor Vincent Hilser said that “what is clear is understanding how these things work is a critical step toward that."
Intrinsically disordered proteins are not like proteins that are familiar to us, but about 40 percent of all proteins are in this group! An especially important characteristic of these proteins is that they are very much involved in transcription, part of the process that turns genes from our genetic material into proteins.
Although it is not known exactly how, it is established that errors in transcription are directly related to cancer, noted Hilser.
"It's probably going to be the case that to understand many, if not most, cancers, you're going to have to understand disorder[ed proteins]," he said.
Proteins had been thought of until the 1990s as structured shapes that could alter their conformation after binding to another molecule. Those changes in shape resulted were thought to be related to the functions of proteins. Not all proteins fit this description, however.
Proteins that did not have a three-dimensional conformation were once thought of as aberrations or artifacts that did not hold real biological significance. Since then, researchers have come to find that these are legitimate proteins, even though they don’t fold up, floating around like strands of pasta. They were thus termed intrinsically disordered.
Since the function of a protein was thought to be dictated by its structure, many questions surrounded these disordered proteins. A team of scientists from Johns Hopkins University with a researcher from the University of Houston aimed to learn more about these proteins.
For this work, they focused on the glucocorticoid receptor, a disordered protein found in human cells. It acts to regulate genes that function in metabolism and immunity, among other things.
They found that one part of the protein is able to act on another. The disordered protein made many versions of itself, acting as regulator molecules that governed its own actions. With an activation-repression dynamic, portions of the disordered chain can self-regulate or regulate other proteins.
"Our work uncovered the language of how these spaghetti pieces communicate," Hilser said. "We showed that those pieces of spaghetti interact with each other sort of like attracting and repulsing magnets, creating a kind of 'tug-of-war,' and that the body can make different versions of the protein to tune which part wins the tug of war."
He said that we still have to explain how proteins and sub-sections are interacting, and how the research will be applied to disease therapeutics that aim to correct errors in that system.
You can see an interview with Hilser above, or check out a video discussing intrinsically disorder proteins, below.