Key Signaling Protein Boasts Multiple, Functionally Different Forms In a paper published in today’s issue of the journal Science, scientists at the University of California, San Diego School of Medicine and Howard Hughes Medical Institute report that variations in the structure of full length protein kinase A or PKA – a major signaling protein involved in regulating numerous important biological processes in mammalian cells – reveal functionally different isoforms of the protein.   “We are describing a new paradigm for thinking about PKA signaling,” said Susan S. Taylor, PhD, a professor in the department of chemistry and biochemistry and the department of pharmacology, and a Howard Hughes Medical Institute Investigator. Taylor and colleagues detail the structure of a full-length, tetrameric (four-part) RIIb holoenzyme of a cAMP-dependent PKA, whose functions include regulating metabolism, ion channels, transporters, and receptors within cells. The specific PKA form studied is abundantly found in fat tissue and in the brain. Depletion of the RIIb isoforms gives a lean phenotype and resistance to diet-induced obesity.  “What is most striking are the differences in quaternary structure between this isoform and the model of the RIa tetramer,” said Taylor. “These differences are likely to be functionally important and help to explain why the four PKA isoforms are not functionally redundant.  It is the tetramer represents the physiological state of the enzyme.” The researchers’ next step will be to correlate the structural differences with functional consequences. Funding for this research came, in part, from the National Institutes of Health. Co-authors are Ping Zhang, Howard Hughes Medical Institute; Eric V. Smith-Nguyen and Michael S. Deal, Department of Chemistry and Biochemistry, UC San Diego; Malik M. Keshwani, Howard Hughes Medical Institute and Department of Pharmacology, UC San Diego; and Alexandr P. Kornev, Department of Chemistry and Biochemistry and Department of Pharmacology, UC San Diego.
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Key Signaling Protein Boasts Multiple, Functionally Different Forms

In a paper published in today’s issue of the journal Science, scientists at the University of California, San Diego School of Medicine and Howard Hughes Medical Institute report that variations in the structure of full length protein kinase A or PKA – a major signaling protein involved in regulating numerous important biological processes in mammalian cells – reveal functionally different isoforms of the protein.  

“We are describing a new paradigm for thinking about PKA signaling,” said Susan S. Taylor, PhD, a professor in the department of chemistry and biochemistry and the department of pharmacology, and a Howard Hughes Medical Institute Investigator.

Taylor and colleagues detail the structure of a full-length, tetrameric (four-part) RIIb holoenzyme of a cAMP-dependent PKA, whose functions include regulating metabolism, ion channels, transporters, and receptors within cells. The specific PKA form studied is abundantly found in fat tissue and in the brain. Depletion of the RIIb isoforms gives a lean phenotype and resistance to diet-induced obesity. 

“What is most striking are the differences in quaternary structure between this isoform and the model of the RIa tetramer,” said Taylor. “These differences are likely to be functionally important and help to explain why the four PKA isoforms are not functionally redundant.  It is the tetramer represents the physiological state of the enzyme.”

The researchers’ next step will be to correlate the structural differences with functional consequences.

Funding for this research came, in part, from the National Institutes of Health.

Co-authors are Ping Zhang, Howard Hughes Medical Institute; Eric V. Smith-Nguyen and Michael S. Deal, Department of Chemistry and Biochemistry, UC San Diego; Malik M. Keshwani, Howard Hughes Medical Institute and Department of Pharmacology, UC San Diego; and Alexandr P. Kornev, Department of Chemistry and Biochemistry and Department of Pharmacology, UC San Diego.

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