Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Structure from Disorder

21.06.2013
Many proteins work like Swiss Army knives, fitting multiple functions into their elaborately folded structures.

A bit mysteriously, some proteins manage to multitask even with structures that are unfolded and floppy—“intrinsically disordered.” In this week’s issue of Nature, scientists at The Scripps Research Institute (TSRI) report their discovery of an important trick that a well-known intrinsically disordered protein (IDP) uses to expand and control its functionality.

“We’ve found what is probably a general mechanism by which IDPs modulate their activities,” said TSRI Professor Peter E. Wright, who is Cecil H. and Ida M. Green Investigator in Biomedical Research and member of TSRI’s Skaggs Institute for Chemical Biology. Wright was a senior investigator for the study, along with TSRI Associate Professor Ashok A. Deniz.

The study focused on an IDP known as the adenovirus “early region 1A oncoprotein” (E1A). An adenovirus starts producing copies of E1A shortly after it infects a cell. E1A proteins interact with a variety of key cellular molecules to quickly subvert the cell’s replication machinery for the benefit of the virus.

Links to Disease

E1A is worth studying not just because it facilitates adenovirus infections, but also because it’s a prime example of an IDP. Such proteins frequently play outsized roles in cells, as crucial “molecular hubs” within very large protein-interaction networks. IDPs also include proteins that are linked to major diseases, including the tumor suppressor protein p53, the alpha synuclein protein of Parkinson’s disease, and the amyloid beta and tau proteins of Alzheimer’s disease.

The simple, flexible structures of IDPs are often promiscuously “sticky,” which in principle explains why they would have multiple molecular partners. But IDPs don’t connect willy-nilly with other proteins, and scientists have wondered how they regulate their diverse interactions.

Wright’s laboratory and others have been studying these interactions using a technique called nuclear magnetic resonance (NMR) spectroscopy. However, E1A’s intrinsic stickiness means that it tends to aggregate at NMR-friendly concentrations, rendering this method of analysis problematic. (Most proteins, by folding up into complex shapes, effectively cloak their stickier bits.)

A Sensitive Technique

For the new study, Wright and his colleagues turned to Deniz, whose laboratory specializes in the use of sensitive, cutting-edge techniques to study the dynamics of disordered proteins and other biological molecules. One of these techniques, a quantum optics method known as single-molecule FRET, uses a tiny fluorescent beacon system to register distances between selected parts of a protein. In effect, this allows investigators to monitor in real time the shape-changes of E1A—characterized by Wright’s laboratory in earlier work—which mark its rapid couplings and uncouplings with other proteins.

“The technique is sensitive enough that we can use it at extremely low protein concentrations, even focusing on single E1A proteins to avoid the loss of information that comes from the usual averaging of results over multiple proteins,” Deniz said.

Postdoctoral fellows Allan Chris M. Ferreon and Josephine C. Ferreon, in the Deniz and Wright laboratories, respectively, used the single-molecule FRET method to detail the strengths (“affinities”) with which E1A binds to two of its most important protein partners. By mapping how these binding affinities change under different conditions, they were able to obtain key insights into how E1A manages its multiple interactions.

Achieving Complexity

First, like many folded proteins, E1A turns out to employ a basic regulatory mechanism called allostery: when one protein partner binds at one part of the E1A structure, it changes the ability of the other major binding site on E1A to bind other partners.

For most proteins that use allostery, this change makes partner-binding at the other site more likely (“positive cooperativity”). For a minority, it makes partner-binding at the other site less likely (“negative cooperativity”). But E1A turns out to have the capacity for either positive cooperativity or negative cooperativity between its two major binding regions—depending on whether a third part of the protein is occupied. “Allostery itself is a mechanism for modulating a protein’s functions, and here we show that E1A takes it to another level by modulating allostery—modulating the modulation, in effect,” said Josephine Ferreon.

The finding helps explain how E1A generates and manages its functional complexity—a complexity that for viral proteins seems particularly necessary, considering how tiny viral genomes are in comparison to those of their animal hosts. Moreover, some of E1A’s key binding partners in infected cells are themselves hub-type IDPs. “So now you multiply the complexity—and you can see how proteins such as E1A manage to achieve so much so quickly within a cell,” said Allan Ferreon.

Wright regards the study as the start of a rewarding line of investigation using sensitive techniques such as single-molecule FRET. “The fact that we can get around the usual technical obstacles relating to IDPs and do these single-molecule experiments really opens up the study of IDP hub interactions,” he said.

Deniz concludes, “We’re definitely going to be studying more of these hub proteins, and I think we’re going to discover other fundamental principles by which they achieve complex layers of biological regulation and function.”

The study, “Modulation of allostery by protein intrinsic disorder” was funded by the National Institutes of Health (grants GM066833 and CA96865) and by the Skaggs Institute for Chemical Biology at TSRI.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

Mika Ono | Newswise
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>