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

Bachmaier, S., Santos, Y. V., Kramer, S., Githure, G. B., Kloeckner, T., Pepperl, J., et al. (2019). Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma. Nature Communications, 10: 1421. doi:10.1038/s41467-019-09338-z.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-E6CA-6 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-E6CB-5
Genre: Journal Article

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 Creators:
Bachmaier, Sabine1, Author
Santos, Yuri Volpato1, Author
Kramer, Susanne1, Author
Githure, George Boniface1, Author
Kloeckner, Thomas1, Author
Pepperl, Julia1, Author
Baums, Cordula1, Author
Schenk, Robin1, Author
Schwede, Frank1, Author
Genieser, Hans-Gottfried1, Author
Dupuy, Jean-William1, Author
Forne, Ignasi1, Author
Imhof, Axel1, Author
Basquin, Jerome2, Author              
Lorentzen, Esben1, Author
Boshart, Michael1, Author
Affiliations:
1external, ou_persistent22              
2Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565144              

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Free keywords: NUCLEOTIDE-BINDING DOMAINS; REGULATORY SUBUNIT; PYRROLOPYRIMIDINE NUCLEOSIDES; AFRICAN TRYPANOSOMES; RNA INTERFERENCE; BRUCEI; PHOSPHODIESTERASE; EXPRESSION; SEQUENCE; PATHWAYScience & Technology - Other Topics;
 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-deazanucleosides as potent activators (EC50 >= 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 alpha D 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.

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Language(s): eng - English
 Dates: 2019
 Publication Status: Published online
 Pages: 14
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 10 Sequence Number: 1421 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723