PKA catalytic subunit mutations in adrenocortical Cushing's adenoma impair association with the regulatory subunit

Davide Calebiro, Cristina Ronchi, Annette Hannawacker, Sandra Lyga, Kerstin Bathon, Ulrike Zabel, Felix Beuschlein, Martin Reincke, Kristina Lorenz, Bruno Allolio, Caroline Kisker, Martin Fassnacht, Martin J. Lohse

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41 Citations (Scopus)
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Abstract

We recently identified a high prevalence of mutations affecting the catalytic (Cα) subunit of protein kinase A (PKA) in cortisol-secreting adrenocortical adenomas. The two identified mutations (Leu206Arg and Leu199-Cys200insTrp) are associated with increased PKA catalytic activity, but the underlying mechanisms are highly controversial. Here we utilize a combination of biochemical and optical assays, including fluorescence resonance energy transfer in living cells, to analyze the consequences of the two mutations with respect to the formation of the PKA holoenzyme and its regulation by cAMP. Our results indicate that neither mutant can form a stable PKA complex, due to the location of the mutations at the interface between the catalytic and the regulatory subunits. We conclude that the two mutations cause high basal catalytic activity and lack of regulation by cAMP through interference of complex formation between the regulatory and the catalytic subunits of PKA.

Original languageEnglish
Article number5680
Number of pages7
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 5 Dec 2014

Keywords

  • Adrenal tumours
  • Biochemistry
  • Mutation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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