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Protein kinase A (PKA) is an enigmatic enzyme playing an essential role in metabolism, cell growth, memory formation, cell signalling, and heart function, for instance. Errant prolonged activation is implicated in cardiac disease and breast cancer. Now, US scientists have obtained an X-ray crystal structure of the dynamic regulatory subunit of PKA, which could shed light on its mode of action. PKA has an amazing ability to function as a "scaffold", supporting and controlling the release of chemicals involved in cell signalling. Susan Taylor, Choel Kim, Cecilia Cheng, and Adrian Saldana of the University of California, San Diego (UCSD) School of Medicine have now shown how PKA is activated and inhibited by the ubiquitous biomolecule cAMP (cyclic adenosine monophosphate). PKA contains two components, the regulatory and catalytic subunits. When the subunits are together in the absence of cAMP, signalling is switched off; when cAMP activates the two parts they break apart switching on PKA is. "We knew how the two subunits, the catalytic and regulatory subunits, looked as separate entities," says Taylor, "But we didn't understand how they actually fit together and are activated by cAMP until we saw this structure." Taylor confesses that the team was surprised by just how much the PKA structure changes in deactivation. "The regulatory subunit opens up and literally wraps itself around the catalytic subunit," she explains, "thus completely turning the signal off." The crystal structure will allow drug designers to target the enzyme more specifically in searching for new treatments for cancer or heart disease. Taylor's work on cAMP-dependent protein kinase, the archetype of this group of enzymes of which there are more than 500 in all multi-cellular organisms, including humans, is world-renowned. In 1991, she and her colleagues published the first structure of the catalytic subunit of a protein kinase, one involved in the action of adrenalin within cells. At the time, the structure was described as a biological Rosetta stone, which has enabled much of the structural and mechanistic work into protein kinases ever since. Related links:
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