Proteomics

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Label-free, quantitative analysis of PKA-dependent phosphoproteome changes in Trypanosoma brucei


ABSTRACT: Protein kinase A (PKA), the main effector of second messenger cAMP, is highly conserved among eukaryotes and a paradigm for the mechanisms of regulation of protein kinases by ligands. The unique PKA holoenzymes in the phylogenetically distant protozoan parasite Trypanosoma are unresponsive to cAMP in vitro and in vivo. By small molecule screening and optimization, we designed direct, membrane-permeable activators binding with a kD of 9 nM to the CNB pockets of the T. brucei regulatory PKA subunit. 7-Cyano-7-deazainosine has low toxicity and thus is a perfect tool to explore cAMP-independent PKA signaling in these important pathogens. This project describes PKA-induced phosphoproteome changes of the bloodstream stage of T. brucei.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Trypanosoma Brucei

SUBMITTER: Ignasi Forne  

LAB HEAD: Prof. Dr. Michael Boshart (Genetics, Biochemistry, Cell Biology) Prof. Dr. Michael Boshart

PROVIDER: PXD012245 | Pride | 2019-02-25

REPOSITORIES: Pride

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Publications


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<sub>50</sub> ≥ 6.5 nM) and high affinity ligands (K<sub>D</sub> ≥ 8 nM). A co-crystal structure of trypanosome PKA with 7-cyano-7-deazainosine and molecular docking show how substitution of key amin  ...[more]

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