Researchers Discover New Data on Protein Kinase A

By employing X-rays and neutron beams, a team of researchers have gleaned new information about protein kinase A (PKA), an omnipresent master control protein that helps regulate basic cellular functions such as energy consumption and interactions with neurotransmitters, hormones, and drugs.

The scientists who conducted the study were from the University of California (UC), San Diego School of Medicine (USA), University of Utah (Salt Lake City, USA), and Oak Ridge US National Laboratory (Oak Ridge, TN, USA). “Mutations in PKA can lead to a variety of different human diseases, including cancers, metabolic and cardiovascular diseases and diseases involving the brain and nervous system,” said senior author Susan Taylor, PhD, professor of chemistry, biochemistry and pharmacology at UC San Diego and international authority on PKA. “Developing treatments and cures for these diseases depends upon knowing how the switch works.”

The findings were published October 10, 2014, issue of the Journal of Biological Chemistry. The researchers concentrated on one of four types of PKA called II-beta, which is found mostly in the brain and in fat, where it may play a significant role in obesity and diet-induced insulin-resistance associated with type 2 diabetes. All forms of PKA are regulated by a signaling molecule called cyclic adenosine monophosphate (cAMP). Many cellular functions are based upon altering amounts of cAMP within cells. PKA is the molecular sensor for cAMP, modulating cell activity according to cAMP levels.

The scientists investigated which parts of the II-beta protein were needed to determine its overall shape, internal construction and ability to change shape—factors that control function. II-beta is very compact when inactive but extends and separates into subunits when it senses cAMP. “A key question regarding the architecture of the II-beta was whether both of its cAMP-sensing mechanisms were needed for the unique changes in shape that it undergoes with cAMP,” said first author Donald K. Blumenthal, PhD, associate professor of pharmacology and toxicology at the University of Utah College of Pharmacy.

Researchers removed one of II-beta’s cAMP sensors and then documented its ability to change shape in response to cAMP, using small-angle X-ray and advanced neutron scattering imaging technologies at Oak Ridge’s high flux isotope reactor in Tennessee. They discovered that the protein could still change shape with just one sensor and that its internal architecture stayed similar to II-beta protein with both its cAMP sensors.

The findings further narrow and define the major components of II-beta and identify new areas for further investigation. Prof. Taylor reported that the collaborative, multi-team effort also demonstrated the importance of using different techniques in an iterative way to unravel the dynamic characteristics of complex systems.

Related Links:
University of California, San Diego School of Medicine 
University of Utah
Oak Ridge US National Laboratory