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The Regulatory Subunit Type Iα of Protein Kinase A: A Study of Carney Complex and Acrodysostosis Mutations
Author(s) -
Del Rio Jason C,
Nielsen Cole R.,
Taylor Susan S.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.765.15
Subject(s) - protein subunit , allosteric regulation , protein kinase a , biology , gene , mutation , kinase , gi alpha subunit , microbiology and biotechnology , genetics , receptor
cAMP‐dependent Protein Kinase A (PKA), a tetrameric holoenzyme comprised of two Catalytic (C) and one dimer of Regulatory (R) subunits, is the prototypical kinase in response to intracellular cAMP. Of the four functionally non‐redundant R subunits (RIa, RIb, RIIa, RIIb), RIa is the dominant, ubiquitously expressed isoform and is the only R subunit which is embryonic lethal in homozygous mouse knockout models due to defective cardiogenesis at E8.5. Recently, two rare phenotypically dichotomous diseases have been linked to mutations in the same gene encoding RIa. Hindering the capacity of RIα to bind and respond to cAMP results in overregulation (inhibition) of the C subunit, a rare condition called Acrodysostosis type I (ACRDYS1), where patients display severe skeletal defects, mental retardation, and hormonal resistance. In contrast, patients with gain of function mutations result in Carney Complex (CNC) disease, caused by under‐regulation of C subunit activity, and present with lentigenosis, recurrent cutaneous and cardiac myxomas, and a Cushings‐like endocrinopathy. While the majority of CNC mutations result in happloinsufficiency via nonsense mediated decay (NMD), the mutations which survive NMD implore multiple mechanisms for disease manifestation. Using these disease mutations with functional effects of opposite magnitude will provide insight into the allosteric communication networks present within the RIa subunit necessary to tightly regulate the critical and finely tuned PKA signaling node for biological processes. Furthermore, structural studies of these two rare diseases will provide a pharmacological platform for rational drug design in their treatment. Support or Funding Information JCDR was supported in part by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology through an institutional training grant from the National Institute of General Medical Sciences, T32 GM007752