Phosphoprotein phosphatase of Mycobacterium tuberculosis dephosphorylates serine–threonine kinases PknA and PknB

Chopra, Puneet; Singh, Bhuminder; Singh, Ramandeep; Vohra, Reena; Koul, Anil; Meena, Laxman S.; Koduri, Harshavardhan; Ghildiyal, Megha; Deol, Parampal; Das, Taposh K.; Tyagi, Anil K.; Singh, Yogendra

doi:10.1016/j.bbrc.2003.09.173

Cited by 58 publications

(58 citation statements)

References 25 publications

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“…However, a deletion of S. pneumoniae PhpP could be obtained when the eSTK (StkP) located in the same operon was also deleted, suggesting that an important role of these phosphatases is to modulate the autophosphorylation state of their partner kinases (131). For example, autophosphorylated StkP is a substrate for PhpP (125), the kinase activity of autophosphorylated M. tuberculosis PknB is reduced by PstP-mediated dephosphorylation (18,26), B. subtilis PrpC dephosphorylates PrkC in vitro (127), the enzymatic function of the Bacillus anthracis eSTK Ba-Stk1 is reduced after desphosphorylation by the eSTP Ba-Stp1 (161), and a strong interaction was reported between the M. xanthus eSTP Pph1 and the eSTK Pkn5 (180). In some cases, however, the eSTP target is a noncognate kinase.…”

Section: Ppm Family Estpsmentioning

confidence: 99%

Eukaryote-Like Serine/Threonine Kinases and Phosphatases in Bacteria

Pereira

Goss

Dworkin

2011

Microbiol Mol Biol Rev

327

348

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SUMMARY Genomic studies have revealed the presence of Ser/Thr kinases and phosphatases in many bacterial species, although their physiological roles have largely been unclear. Here we review bacterial Ser/Thr kinases (eSTKs) that show homology in their catalytic domains to eukaryotic Ser/Thr kinases and their partner phosphatases (eSTPs) that are homologous to eukaryotic phosphatases. We first discuss insights into the enzymatic mechanism of eSTK activation derived from structural studies on both the ligand-binding and catalytic domains. We then turn our attention to the identified substrates of eSTKs and eSTPs for a number of species and to the implications of these findings for understanding their physiological roles in these organisms.

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Section: Ppm Family Estpsmentioning

confidence: 99%

Eukaryote-Like Serine/Threonine Kinases and Phosphatases in Bacteria

Pereira

Goss

Dworkin

2011

Microbiol Mol Biol Rev

327

348

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“…PstP efficiently dephosphorylates a variety of phosphorylated proteins, including PknA and PknB (17,18) as well as other M. tuberculosis STPK domains (42). Dephosphorylation of STPKs simultaneously abolishes binding sites for substrates containing FHA domains (22) and substantially reduces protein kinase activity (18).…”

Section: Journal Of Biological Chemistry 30099mentioning

confidence: 99%

“…Nine of these gene products are predicted to be membrane proteins, presenting a sensor domain to the extracellular face and a kinase catalytic domain to the cytoplasm (11). All mycobacterial Ser/Thr kinases described to date display autophosphorylation activity, and several exogenous substrates have been reported to be phosphorylated by these enzymes (13)(14)(15)(16)(17)(18)(19)(20)(21). Our understanding of STPKs/substrate interactions in mycobacteria remains limited, because only a few endogenous substrates have been reported, most of them being recognized by virtue of being encoded by genes close to their cognate STPK genes (22)(23)(24)(25)(26).…”

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confidence: 99%

The Condensing Activities of the Mycobacterium tuberculosis Type II Fatty Acid Synthase Are Differentially Regulated by Phosphorylation

Molle

Brown

Besra

et al. 2006

Journal of Biological Chemistry

105

119

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Phosphorylation of proteins by Ser/Thr protein kinases (STPKs) has recently become of major physiological importance because of its possible involvement in virulence of bacterial pathogens. Although Mycobacterium tuberculosis has eleven STPKs, the nature and function of the substrates of these enzymes remain largely unknown. In this work, we have identified for the first time STPK substrates in M. tuberculosis forming part of the type II fatty acid synthase (FAS-II) system involved in mycolic acid biosynthesis: the malonyl-CoA::AcpM transacylase mtFabD, and the ␤-ketoacyl AcpM synthases KasA and KasB. All three enzymes were phosphorylated in vitro by different kinases, suggesting a complex network of interactions between STPKs and these substrates. In addition, both KasA and KasB were efficiently phosphorylated in M. bovis BCG each at different sites and could be dephosphorylated by the M. tuberculosis Ser/Thr phosphatase PstP. Enzymatic studies revealed that, whereas phosphorylation decreases the activity of KasA in the elongation process of long chain fatty acids synthesis, this modification enhances that of KasB. Such a differential effect of phosphorylation may represent an unusual mechanism of FAS-II system regulation, allowing pathogenic mycobacteria to produce full-length mycolates, which are required for adaptation and intracellular survival in macrophages.Mycobacterium tuberculosis has a unique cell wall structure that accounts for the ability of the bacterium to grow in several contrasting environments and which is responsible for its low membrane permeability, contributing to its resistance to common chemotherapeutic agents (1). The cell wall has been implicated as a direct modulator of interactions between mycobacteria and the environment (2). This envelope, characterized by its high lipid content, comprises an inner membrane barrier composed of mycolic acids anchored to arabinogalactan, linked to peptidoglycan. Mycolic acids are a hallmark of the mycobacterial waxy coat: they represent key virulence factors required for intracellular survival (3, 4) and contribute to the physiopathology of tuberculosis. They consist of very long chains of ␣-branched ␤-hydroxy fatty acids (C 60 -C 90 ), whose biosynthesis is controlled by two elongation systems, the eukaryotic-type fatty acid synthase (FAS-I) 3 and the prokaryotic-like FAS-II (5, 6). FAS-I consists of a single multifunctional polypeptide, catalyzing de novo synthesis of medium length acyl-CoA chains (C 16 -C 26 ), whereas FAS-II comprises several distinct enzymes. It catalyzes similar types of reactions to FAS-I, but functions on acyl carrier protein (AcpM)-bound chains and is incapable of de novo synthesis. The initial substrates of FAS-II are ␤-ketoacylAcpM resulting from the condensation by mtFabH of the acylCoA products of FAS-I with malonyl-AcpM (7, 8). Following reduction by MabA, elimination of water by a yet unidentified dehydratase, and reduction by the enoyl-AcpM reductase InhA, the ␤-ketoacyl-AcpM synthases KasA and KasB catalyze further...

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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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Phosphoprotein phosphatase of Mycobacterium tuberculosis dephosphorylates serine–threonine kinases PknA and PknB

Cited by 58 publications

References 25 publications

Eukaryote-Like Serine/Threonine Kinases and Phosphatases in Bacteria

Eukaryote-Like Serine/Threonine Kinases and Phosphatases in Bacteria

The Condensing Activities of the Mycobacterium tuberculosis Type II Fatty Acid Synthase Are Differentially Regulated by Phosphorylation

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

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