The <i>Mycobacterium tuberculosis</i> protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth <i>in vivo</i>

Cowley, Siobhán C.; Ko, Mary; Pick, Neora; Chow, Rayken; Downing, Katrina; Gordhan, Bhavna G.; Betts, Joanna; Mizrahi, Valerie; Smith, Debbie A.; Stokes, Richard W.; Av‐Gay, Yossef

doi:10.1111/j.1365-2958.2004.04085.x

Cited by 225 publications

(239 citation statements)

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“…4). Experimental reports have suggested functional roles in cell morphology (PknA and -B) (5,6), stress response (PknH) (7), glucose transport (PknF) (8,9), and regulation of cellular Glu͞Gln levels (PknG) (10). However, endogenous substrates could be identified in only a few cases (6,8,11,12).…”

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confidence: 99%

Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis

Alderwick

Molle

Kremer

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Ser͞Thr phosphorylation has emerged as a critical regulatory mechanism in a number of bacteria, including Mycobacterium tuberculosis. This problematic pathogen encodes 11 eukaryoticlike Ser͞Thr kinases, yet few substrates or signaling targets have been characterized. Here, we report the structure of EmbR (2.0 Å), a putative transcriptional regulator of key arabinosyltransferases (EmbC, -A, and -B), and an endogenous substrate of the Ser͞Thr-kinase PknH. EmbR presents a unique domain architecture: the N-terminal winged-helix DNA-binding domain forms an extensive interface with the all-helical central bacterial transcriptional activation domain and is positioned adjacent to the regulatory Cterminal forkhead-associated (FHA) domain, which mediates binding to a Thr-phosphorylated site in PknH. The structure in complex with a phospho-peptide (1.9 Å) reveals a conserved mode of phospho-threonine recognition by the FHA domain and evidence for specific recognition of the cognate kinase. The present structures suggest hypotheses as to how EmbR might propagate the phospho-relay signal from its cognate kinase, while serving as a template for the structurally uncharacterized Streptomyces antibiotic regulatory protein family of transcription factors.PknH ͉ x-ray crystallography ͉ arabinosyltransferase ͉ transcriptional regulator ͉ ethambutol

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confidence: 99%

Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis

Alderwick

Molle

Kremer

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…These two activation mechanisms result in an autophosphorylated active kinase. In contrast, PknG contains phosphorylation sites in the C-terminal domain that may be necessary for activity (30,31). These biochemical and structural insights suggest a general model for activation in which ligand binding to the extracellular domain promotes KD dimerization and intermolecular autophosphorylation (26,32).…”

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confidence: 99%

Biochemical and Spatial Coincidence in the Provisional Ser/Thr Protein Kinase Interaction Network of Mycobacterium tuberculosis*

Baer

Iavarone

Alber

et al. 2014

Journal of Biological Chemistry

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Background: Ser/Thr protein kinases (STPKs) form multilayered signaling networks that mediate cellular responses in eukaryotes and prokaryotes. Results: A preliminary interaction network for the STPKs in Mycobacterium tuberculosis is described. Conclusion: STPKs that cross-phosphorylate are often co-localized, suggesting multiple activation mechanisms. Significance: The initial map of this prokaryotic STPK network provides a framework for defining the logic of M. tuberculosis signaling pathways.

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“…Examples include the essential kinases PknA and PknB, which regulate cell shape and cell wall synthesis via phosphorylation of the cell pole-localized protein Wag31 and the septum-associated penicillin-binding protein PbpA (4)(5)(6). A kinase that has been implicated in TB pathogenesis, PknG, phosphorylates the forkhead-associated (FHA) domain-containing protein GarA, which has been shown to regulate enzymes of central carbon and nitrogen metabolism in a phosphorylation state-specific manner (7)(8)(9).…”

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confidence: 99%

Extensive phosphorylation with overlapping specificity by Mycobacterium tuberculosis serine/threonine protein kinases

Prisic

Dankwa

Schwartz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The Mycobacterium tuberculosis genome encodes 11 serine/threonine protein kinases (STPKs) that are structurally related to eukaryotic kinases. To gain insight into the role of Ser/Thr phosphorylation in this major global pathogen, we used a phosphoproteomic approach to carry out an extensive analysis of protein phosphorylation in M. tuberculosis. We identified more than 500 phosphorylation events in 301 proteins that are involved in a broad range of functions. Bioinformatic analysis of quantitative in vitro kinase assays on peptides containing a subset of these phosphorylation sites revealed a dominant motif shared by six of the M. tuberculosis STPKs. Kinase assays on a second set of peptides incorporating targeted substitutions surrounding the phosphoacceptor validated this motif and identified additional residues preferred by individual kinases. Our data provide insight into processes regulated by STPKs in M. tuberculosis and create a resource for understanding how specific phosphorylation events modulate protein activity. The results further provide the potential to predict likely cognate STPKs for newly identified phosphoproteins.signal transduction | phosphorylation motif | phosphoproteomics A key feature of all living cells is the ability to sense environmental signals and implement adaptive changes. These inputs propagate through complex signal transduction networks whose activity is often regulated by reversible protein phosphorylation. Although Ser/Thr/Tyr protein phosphorylation-based signaling in eukaryotes has been intensively studied, the extent to which this mechanism is used in prokaryotes has only recently begun to be appreciated (1). The number of protein kinases in prokaryotes varies widely. Although many bacteria have only a few or none of these enzymes, some cyanobacteria and streptomycetes have dozens of them (2). Bacteria that do possess Ser/Thr or Tyr kinases often have complex lifestyles and depend on these kinases to regulate critical processes, such as stress adaptation, development, and virulence (2).Mycobacterium tuberculosis is an extraordinarily versatile pathogen that can exist in distinct states in the host, leading to asymptomatic latent tuberculosis (TB) infection in which bacteria are thought to be dormant, or active TB disease in which the organisms are actively replicating. To achieve these different physiologic states M. tuberculosis requires mechanisms to sense a wide range of signals from the host and to coordinately regulate multiple cellular processes. In most bacterial pathogens, the predominant phosphorylation-based signal transduction mechanism is the two-component system. The M. tuberculosis genome, however, encodes 11 Ser/Thr protein kinases (STPKs) and an equal number of two-component system sensor kinases, suggesting that these two phospho-based signaling systems are of comparable importance in this organism (3).Knowledge of the substrates of each of the M. tuberculosis STPKs is essential for understanding their function; however, only a small number of kinase-sub...

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The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo

Cited by 225 publications

References 50 publications

Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis

Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis

Biochemical and Spatial Coincidence in the Provisional Ser/Thr Protein Kinase Interaction Network of Mycobacterium tuberculosis*

Extensive phosphorylation with overlapping specificity by Mycobacterium tuberculosis serine/threonine protein kinases

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