Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma

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  • Sabine Bachmaier, Ludwig-Maximilians-University München
  • ,
  • Yuri Volpato Santos, Ludwig-Maximilians-University München
  • ,
  • Susanne Kramer, Ludwig-Maximilians-University München, Julius-Maximilians-Universitat Wurzburg
  • ,
  • George Boniface Githure, Ludwig-Maximilians-University München
  • ,
  • Thomas Klöckner, Ludwig-Maximilians-University München
  • ,
  • Julia Pepperl, Ludwig-Maximilians-University München
  • ,
  • Cordula Baums, Ludwig-Maximilians-University München
  • ,
  • Robin Schenk, Ludwig-Maximilians-University München
  • ,
  • Frank Schwede, BIOLOG Life Science Institute
  • ,
  • Hans Gottfried Genieser, BIOLOG Life Science Institute
  • ,
  • Jean William Dupuy, Universite Bordeaux
  • ,
  • Ignasi Forné, Ludwig-Maximilians-University München
  • ,
  • Axel Imhof, Ludwig-Maximilians-University München
  • ,
  • Jerôme Basquin, Max Planck Institute of Biochemistry
  • ,
  • Esben Lorentzen
  • Michael Boshart, Ludwig-Maximilians-University München

Protein kinase A (PKA), the main effector of cAMP in eukaryotes, is a paradigm for the mechanisms of ligand-dependent and allosteric regulation in signalling. Here we report the orthologous but cAMP-independent PKA of the protozoan Trypanosoma and identify 7-deaza-nucleosides as potent activators (EC 50 ≥ 6.5 nM) and high affinity ligands (K D ≥ 8 nM). A co-crystal structure of trypanosome PKA with 7-cyano-7-deazainosine and molecular docking show how substitution of key amino acids in both CNB domains of the regulatory subunit and its unique C-terminal αD helix account for this ligand swap between trypanosome PKA and canonical cAMP-dependent PKAs. We propose nucleoside-related endogenous activators of Trypanosoma brucei PKA (TbPKA). The existence of eukaryotic CNB domains not associated with binding of cyclic nucleotides suggests that orphan CNB domains in other eukaryotes may bind undiscovered signalling molecules. Phosphoproteome analysis validates 7-cyano-7-deazainosine as powerful cell-permeable inducer to explore cAMP-independent PKA signalling in medically important neglected pathogens.

Original languageEnglish
Article number1421
JournalNature Communications
Volume10
Issue1
ISSN2041-1723
DOIs
Publication statusPublished - 2019

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