Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


"Disordered" Amino Acids May Really Be There to Provide Wiggle Room for Signaling Protein

Fox Chase researchers first to determine structure in a class of self-regulating proteins

Sections of proteins previously thought to be disordered may in fact have an unexpected biological role — providing certain proteins room to move — according to a study published by researchers at Fox Chase Cancer Center in this month's issue of the journal Structure (Cell Press).

The researchers published the first comprehensive structural study of the protein NHERF1, which serves as a means of bringing together molecular signals between the outer membrane of a cell and the proteins found in the structures that form the cell's cytoskeleton. NHERF1 is representative of a large class of proteins with an array of biological roles, including signaling pathways implicated in diseases such as cystic fibrosis and breast cancer.

"Here we have a molecule that serves an important role in how cells function and survive, but it contains these puzzling 'junk' sequences that don't seem to have any apparent purpose," says the paper's lead author Heinrich Roder, PhD, a structural biologist and senior member of the Fox Chase Cancer Center faculty. "Our work suggests that this disorder is really a way of creating flexibility, allowing the protein to function as a molecular switch, a process that is thought to go wrong in certain diseases."

The NHERF1 proved particularly puzzling to researchers as it contains both known structures and large disordered regions. The structured sections of the protein are comprised of two so-called PDZ domains — components well known to scientists as anchors that can help the protein connect to other proteins and cellular structures — and an ezrin-binding motif, a sequence of amino acids that connects NHREF1 to cellular proteins such as ezrin. Together these structures allow NHERF1 to serve as a signaling adaptor, an important link between different proteins in a pathway. Oddly, researchers have noted that the ezrin-binding motif conveniently fits into a cleft on the surface of the PDZ domains, but assumes a helical structure, which is highly unusual for this class of proteins.

As is typical for human proteins, over one third of the amino acids that make up NHERF1 were predicted to be intrinsically disordered, forming no known structures and matching no known evolutionarily-conserved pattern. According to Roder, it is one of these disordered segments, approximately 100 amino acids long, which enable the protein to work. That is, it allows the PDZ binding module to "bite" its own ezrin-binding tail, effectively shutting the protein down. "The flexibility of the linker and its tendency to be more or less disordered are critical for regulating the balance between internal ("autoinhibitory") forces and external interactions with the protein's signaling partners," Roder says. This idea is reinforced by a recent observation by Zimei Bu, PhD, a Fox Chase researcher a coauthor of this study, who found that enzymatic modification (phosphorylation) of amino acids in the disordered region tips the balance towards the more open, active, form of the protein.

"Evolution has provided researchers with convenient modular structures, areas that are repeated over and over again to make up proteins, and so we tend to dismiss the interspersed disordered sequences that don't seem to have any definable structure," Roder says. "Here we show that the weak molecular interactions in a disorganized protein sequence are essential in giving this protein its unique attributes."

It was also this disorganized domain that made it difficult for researchers to create an accurate model of the entire protein, Roder says. Typically, researchers use a technique called x-ray crystallography, in which they can tell a protein's structure from how crystals made from the protein samples scatter x-rays. The disorganized section of NHREF1 makes it nearly impossible to create the necessary crystals to use this technique. Instead, Roder and colleagues used a technique called nuclear magnetic resonance spectroscopy, which can determine a protein's shape by measuring how the individual atomic nuclei of a protein interact with an intense magnetic field.

Since NMR spectroscopy works best with small proteins — not large flexible molecules like NHREF1 — Roder, his staff scientist Hong Cheng, PhD, and their colleagues came up with an innovative technique that allowed them to look at the protein from numerous angles with the NMR spectrometer, and subtract out the overlapping areas to form a more complete picture of the molecule. This picture enabled them to see what NHREF1 looks like in both its "on" and "off" conformation.

"When it is not working, the protein is in this 'off' conformation until acted upon by outside agents," Roder says. "It is a way for the cell to shut off a signaling pathway when it is not in use."

According to Roder, these findings may provide researchers a new way of looking at proteins like NHERF1 and their physiological role in cells.

Funding for this research comes from grants from the National Cancer Institute, National Institute of Health, American Cancer Society and an appropriation by the Commonwealth of Pennsylvania to the Fox Chase Cancer Center.

Greg Lester | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)

nachricht North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Space observation with radar to secure Germany's space infrastructure

Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.

The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...

Im Focus: Researchers Discover New Anti-Cancer Protein

An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.

The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...

Im Focus: Researchers at Fraunhofer monitor re-entry of Chinese space station Tiangong-1

In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.

Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...

Im Focus: Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.

They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

New solar solutions for sustainable buildings and cities

23.03.2018 | Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

Latest News

For graphite pellets, just add elbow grease

23.03.2018 | Materials Sciences

Unique communication strategy discovered in stem cell pathway controlling plant growth

23.03.2018 | Agricultural and Forestry Science

Sharpening the X-ray view of the nanocosm

23.03.2018 | Physics and Astronomy

Science & Research
Overview of more VideoLinks >>>