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 At last, butterflies get a bigger, better evolutionary tree
16.02.2018 | Florida Museum of Natural History

nachricht New treatment strategies for chronic kidney disease from the animal kingdom
16.02.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

Im Focus: Autonomous 3D scanner supports individual manufacturing processes

Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).

Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Fingerprints of quantum entanglement

16.02.2018 | Information Technology

'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers

16.02.2018 | Health and Medicine

Hubble sees Neptune's mysterious shrinking storm

16.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>