title: PKA RIα homodimer structure reveals an intermolecular interface with implications for cooperative cAMP binding and Carney complex disease.
abstract: The regulatory (R) subunit is the cAMP receptor of protein kinase A. Following cAMP binding, the inactive PKA holoenzyme complex separates into two active catalytic (C) subunits and a cAMP-bound R dimer. Thus far, only monomeric R structures have been solved, which fell short in explaining differences of cAMP binding for the full-length protein as compared to the truncated R subunits. Here we solved a full-length R-dimer structure that reflects the biologically relevant conformation, and this structure agrees well with small angle X-ray scattering. An isoform-specific interface is revealed between the protomers. This interface acts as an intermolecular sensor for cAMP and explains the cooperative character of cAMP binding to the RIα dimer. Mutagenesis of residues on this interface not only leads to structural and biochemical changes, but is also linked to Carney complex disease.
authors: Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Jessica G H
authors: JG
authors: Bruystens
authors: Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Jian
authors: J
authors: Wu
authors: Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Audrey
authors: A
authors: Fortezzo
authors: Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Alexandr P
authors: AP
authors: Kornev
authors: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
authors: Donald K
authors: DK
authors: Blumenthal
authors: Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: staylor@ucsd.edu.
authors: Susan S
authors: SS
authors: Taylor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D056733:Carney Complex / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020134:Catalytic Domain; D002417:Cattle; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000737:chemistry* / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D011994:Recombinant Proteins; D000242:Cyclic AMP