Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Look Inside to Reveal Workings of a Powerful Biochemical Switch

13.10.2014

PKA helps regulate basic cellular functions, leads to disease when mutated

Using X-rays and neutron beams, a team of researchers from the University of Utah, University of California, San Diego School of Medicine and Oak Ridge National Laboratory have revealed the inner workings of a master switch that regulates basic cellular functions, but that also, when mutated, contributes to cancer, cardiovascular disease and other deadly disorders.


A molecular model of the protein, PKA II-beta, based on neutron scattering with solvent contrast is laid over the neutron scattering data from the Bio-SANS instrument at DOE’s HFIR research facility. The neutron beam is in the left behind the grey circle and the scattered neutrons create the pattern in the rest of the background. A research team from ORNL, UCSD, and the University of Utah is using neutron and X-ray data to understand the role of this protein in regulating basic cellular functions. Image credit: William Heller/ORNL

Learning more about how the Protein Kinase A (PKA) switch works will help researchers to understand cellular function and disease, according to Donald K. Blumenthal, Ph.D., associate professor of pharmacology and toxicology at the University of Utah (U of U) College of Pharmacy who led the study. “To develop new drugs and treatments for disease, it’s important to understand how PKA works,” he says. “This study helps us get a clearer picture of how the PKA protein helps regulate cellular function and disease.”

The study, published in the Oct. 10 issue of the Journal of Biological Chemistry as its paper of the week, features research conducted using the Bio-SANS instrument at the Oak Ridge National Laboratory (ORNL) High Flux Isotope Reactor (HFIR), a DOE Office of Science User Facility.

The PKA protein comes in four forms, each of which serves as a sensor for a signaling molecule called cyclic AMP (cAMP). When these forms of PKA sense cAMP, they change shape, which researchers believe is critical in determining how PKA works as a biochemical switch. Many hormones, neurotransmitters and drugs communicate with cells by changing the level of cAMP found within them. Accordingly, PKA helps regulate cellular activity in reaction to different levels of cAMP within cells. Because PKA serves as a master switch in cells, mutations in it lead to a variety of diseases including metabolic disorders, disorders of the brain and nervous system, cancer and cardiovascular ills.

Blumenthal and colleagues focused on a form of PKA called II-beta (two-beta), a protein found mostly in the brain and fat cells that is suspected of being involved in obesity and diet-induced insulin-resistance associated with type 2 diabetes. II-beta contains two structures for sensing cAMP, each of which cause II-beta to change its shape in response to the signaling molecule.

The researchers wanted to know whether both of II-beta’s cAMP-sensing structures are required to determine its ability to change shape – a critical factor for its function. To answer this, they removed one of the cAMP sensors and used small-angle neutron scattering at HFIR, and small-angle X-ray scattering at U of U, each of which reveals information about the shape and size of molecules. The results of the study showed that II-beta does, indeed, change shape with only one sensor.

“By process of elimination, this must mean that parts of the remaining single sensor of II-beta give it its unique shape and internal architecture,” says Susan Taylor, Ph.D., professor of chemistry, biochemistry and pharmacology at the University of California, San Diego, and co-author on the study. “Our findings further narrow and define the key components of II-beta and identify new regions for further study.”

Future research should focus on a part of II-beta called the “linker region,” which connects the remaining cAMP sensor with a part of II-beta that helps target PKA to specific cell locations, according to Blumenthal. “Based on what we know about II-beta and other forms of PKA, it’s likely that the linker region plays a major role in organizing the internal architecture and shape changes determine the unique biological functions of each form of PKA.”

The study’s co-authors include Jeffrey Copps, Eric V. Smith-Nguyen and Ping Zhang, UCSD Department of Chemistry and Biochemistry and Howard Hughes Medical Institute and William T. Heller, Oak Ridge National Laboratory.

Funding support for this research came from the National Institutes of Health (grant GM34921). The Center for Structural Molecular Biology operates Bio-SANS, the HFIR instrument used for the neutron scattering experiments, and is supported by the DOE Office of Science, which also supports HFIR.

UT-Battelle manages ORNL for the Department of Energy's Office of Science. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit http://science.energy.gov/.

Contact Information

Katie Bethea
Oak Ridge National Laboratory
865-576-8039
betheakl@ornl.gov

Katie Bethea | newswise

More articles from Life Sciences:

nachricht Closing the carbon loop
08.12.2016 | University of Pittsburgh

nachricht Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Closing the carbon loop

08.12.2016 | Life Sciences

Applicability of dynamic facilitation theory to binary hard disk systems

08.12.2016 | Physics and Astronomy

Scientists track chemical and structural evolution of catalytic nanoparticles in 3-D

08.12.2016 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>