Unlocking mystery of protein function

November 27, 2017, Johns Hopkins University

What makes the body of a person or any other organism work can for the most part be summed up in a word: proteins.

These big carry out almost all processes in , including moving other molecules from one place to another, replicating DNA, conveying from genes to cells, controlling , driving metabolism and building muscle. Not all molecules are created equal, though, and some are better understood than others.

Now, a team of scientists led by a Johns Hopkins University biologist has cracked a key part of the mystery surrounding proteins that emerged as a distinct type less than 30 years ago. The finding reported in the online journal eLife could eventually lead to treatments for diseases that range from cancer to neurological disorders.

Vincent Hilser, professor and chair of the Johns Hopkins Department of Biology, said it's not possible to say when this new research will translate into improved treatments, "but what is clear is understanding how these things work is a critical step toward that."

These so-called "" do not look like the more familiar type, but they make up about 40 percent of all proteins. Perhaps more important, they constitute the majority of proteins involved in the process called "transcription." That's how the instructions in genetic code are conveyed to cells and ultimately body tissues.

It is not clear exactly how errors in transcription affect human health, but it is known that these errors are involved in most cancers, Hilser said.

"It's probably going to be the case that to understand many, if not most, cancers, you're going to have to understand disorder," he said, meaning disordered proteins.

Until the early 1990s, scientists only knew of "structured" proteins, existing as unique shapes that respond when a regulator molecule binds to them, changing their shape and controlling their function. These have been compared to origami creations folded into a particular shape.

Anything showing up in experiments that did not fit that profile was often dismissed as some problem with the experiment, or an anomalous form that was not biologically significant.

These outliers have since been recognized as a legitimate form of protein, although given a somewhat disparaging name. They don't fold up, they don't assume any unique shape at all other than strands of "spaghetti," as Hilser puts it. Hence the "disorder" in the name, as opposed to "structured" proteins - and part of the mystery.

If the structure is the mark of the regulating molecule doing its work - determining and function - then what to make of proteins that do not do that? What controls the activities of these shapeless strands?

The scientists, nine from Johns Hopkins and one from the University of Houston, set out to answer the question. They chose for their study a disordered protein taken from human cells called glucocorticoid receptor, which regulates genes that control, among other functions, metabolism and immune system response.

By manipulating segments of the protein in the lab, they were able to show how one portion acts on another, and that the disordered protein creates versions of itself to act almost in place of regulator molecules that govern its activity. The disordered protein uses an activation-repression dynamic between sections within the disordered chain to regulate its own activities and those of 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."

Yet to be explained, he said, is how the interactions among these proteins and the sub-sections happen and how all this can ultimately be used to treat disorders that emerge when things go awry with these molecules central to almost all life function.

Explore further: New protein study broadens knowledge of molecular basis for disease

More information: Jing Li et al, Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor, eLife (2017). DOI: 10.7554/eLife.30688

Related Stories

Ancient proteins studied in detail

May 8, 2017

How did protein interactions arise and how have they developed? In a new study, researchers have looked at two proteins which began co-evolving between 400 and 600 million years ago. What did they look like? How did they ...

Recommended for you

Simulations show how beta-amyloid may kill neural cells

May 25, 2018

Beta-amyloid peptides, protein fragments that form naturally in the brain and clump into plaques in Alzheimer's disease patients, are thought to be responsible for neuron death, but it hasn't been clear how the substances ...

Why bioelectrodes for energy conversion are not stable

May 25, 2018

Researchers at the Ruhr-Universität Bochum have discovered why bioelectrodes containing the photosynthesis protein complex photosystem I are not stable in the long term. Such electrodes could be useful for converting light ...

The changing shape of DNA

May 24, 2018

The shape of DNA can be changed with a range of triggers including copper and oxygen—according to new research from the University of East Anglia.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.