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

Author

Listed:
  • Sabine Bachmaier

    (Ludwig-Maximilians-University Munich (LMU))

  • Yuri Volpato Santos

    (Ludwig-Maximilians-University Munich (LMU))

  • Susanne Kramer

    (Ludwig-Maximilians-University Munich (LMU)
    University of Würzburg)

  • 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))

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.

Suggested Citation

  • Sabine Bachmaier & Yuri Volpato Santos & Susanne Kramer & George Boniface Githure & Thomas Klöckner & Julia Pepperl & Cordula Baums & Robin Schenk & Frank Schwede & Hans-Gottfried Genieser & Jean-Will, 2019. "Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09338-z
    DOI: 10.1038/s41467-019-09338-z
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    Cited by:

    1. Michael P. Andreas & Tobias W. Giessen, 2024. "The biosynthesis of the odorant 2-methylisoborneol is compartmentalized inside a protein shell," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Sabine Bachmaier & Giacomo Giacomelli & Estefanía Calvo-Alvarez & Larissa Rezende Vieira & Jan Abbeele & Aris Aristodemou & Esben Lorentzen & Matt K. Gould & Ana Brennand & Jean-William Dupuy & Ignasi, 2022. "A multi-adenylate cyclase regulator at the flagellar tip controls African trypanosome transmission," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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