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

Sabine Bachmaier, Yuri Volpato Santos, Susanne Kramer, George Boniface Githure, Thomas Klöckner, Julia Pepperl, Cordula Baums, Robin Schenk, Frank Schwede, Hans-Gottfried Genieser, Jean-William Dupuy, Ignasi Forné, Axel Imhof, Jerôme Basquin, Esben Lorentzen and Michael Boshart ()
Additional contact information
Sabine Bachmaier: Ludwig-Maximilians-University Munich (LMU)
Yuri Volpato Santos: Ludwig-Maximilians-University Munich (LMU)
Susanne Kramer: Ludwig-Maximilians-University Munich (LMU)
George Boniface Githure: Ludwig-Maximilians-University Munich (LMU)
Thomas Klöckner: Ludwig-Maximilians-University Munich (LMU)
Julia Pepperl: Ludwig-Maximilians-University Munich (LMU)
Cordula Baums: Ludwig-Maximilians-University Munich (LMU)
Robin Schenk: Ludwig-Maximilians-University Munich (LMU)
Frank Schwede: BIOLOG Life Science Institute
Hans-Gottfried Genieser: BIOLOG Life Science Institute
Jean-William Dupuy: Université Bordeaux
Ignasi Forné: Ludwig-Maximilians-University Munich (LMU)
Axel Imhof: Ludwig-Maximilians-University Munich (LMU)
Jerôme Basquin: Max Planck-Institute for Biochemistry
Esben Lorentzen: Aarhus University
Michael Boshart: Ludwig-Maximilians-University Munich (LMU)

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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 (EC50 ≥ 6.5 nM) and high affinity ligands (KD ≥ 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.

Date: 2019
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DOI: 10.1038/s41467-019-09338-z

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