Phosphorylation of Mycobacterium tuberculosis protein tyrosine kinase A PtkA by Ser/Thr protein kinases

Zhou, Peifu; Wong, Dennis; Wu, Li; Xie, Jianping; Av‐Gay, Yossef

doi:10.1016/j.bbrc.2015.09.124

Cited by 16 publications

(15 citation statements)

References 41 publications

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“…The mycobacterial tyrosine phosphatase PtpA, is also a substrate of PknA and similar to PstP, phosphorylation enhances its activity . The only reported tyrosine kinase PtkA is phosphorylated by multiple kinases including PknA , however, the role of this phosphorylation on its activity has not been investigated. Together these reports suggest that PknA modulates the cellular processes directly by phosphorylating enzymes involved in the cell wall and cell division processes and indirectly through modulating the activities of phosphatases.…”

Section: Introductionmentioning

confidence: 99%

Targeting the messengers: Serine/threonine protein kinases as potential targets for antimycobacterial drug development

2018

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The emergence of increasingly drug-resistant Mycobacterium tuberculosis strains has become a crucial public health concern. In order to effectively treat tuberculosis, it is imperative to find newer drug targets, which are important for the in vivo bacterial survival and persistence. Phosphorylation based signaling cascades modulated by eukaryotic-like serine/threonine protein kinases and phosphatase in M. tuberculosis, transduce extracellular stimuli to a cellular response ensuing pathogen's growth, persistence and pathogenesis. Of the 11 STPKs that M. tuberculosis genome encodes, three kinases, namely PknA, PknB and PknG and the sole serine/threonine phosphatase PstP are crucial for the intracellular survival of the bacteria. PknA and PknB regulates cell growth, cell wall synthesis and morphological changes during bacterial cell division; while PknG modulates metabolic changes in response to stress and aids in bacterial survival during latency like conditions. PstP functions to dephosphorylate STPKs and their substrates and hence is important at nearly all stages of infection. Here, we review the current knowledge on PstP, PknA, PknB and PknG based on the genetic, biochemical, and functional studies in M. tuberculosis physiopathology. We further explore the potential of these molecules as targets for therapeutic intervention and discuss the advancement made in the development of inhibitors against these targets. © 2018 IUBMB Life, 70(9):889-904, 2018.

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Section: Introductionmentioning

confidence: 99%

Targeting the messengers: Serine/threonine protein kinases as potential targets for antimycobacterial drug development

2018

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“…Threonine‐specific phosphorylation of PtkA by Mtb endogenus eSTPK was recently reported . Previous studies by Husson et al .…”

Section: Resultsmentioning

confidence: 82%

“…Threonine-specific phosphorylation of PtkA by Mtb endogenus eSTPK was recently reported [34]. Previous studies by Husson et al propose serine/threonine specific phosphorylation as an important regulatory mechanism of Mtb virulence [35].…”

Section: Phosphorylation-induced Conformational Changesmentioning

confidence: 89%

Structural characterization of the intrinsically disordered domain of Mycobacterium tuberculosis protein tyrosine kinase A

et al. 2018

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Although intrinsically disordered proteins or protein domains (IDPs or IDD) are less abundant in bacteria than in eukaryotes, their presence in pathogenic bacterial proteins is important for protein-protein interactions. The protein tyrosine kinase A (PtkA) from Mycobacterium tuberculosis possesses an 80-residue disordered region (IDD ) of unknown function, located N-terminally to the well-folded kinase core domain. Here, we characterize the conformation of IDD under varying biophysical conditions and phosphorylation using NMR-spectroscopy. Our results confirm that the N-terminal domain of PtkA exists as an IDD at physiological pH. Furthermore, phosphorylation of IDD increases the activity of PtkA. Our findings will complement future approaches in understanding molecular mechanisms of key proteins in pathogenic virulence.

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“…In particular, Tyr 262 was considered as the target for phosphorylation during autocatalysis (18). PtkA itself represents a target protein for phosphorylation by the Mtb endogenous STPK (20). We inves-Structural studies of PtkA by NMR tigated (i) the autophosphorylation of PtkA, (ii) the effect of Mg 2ϩ , (iii) interactions between PtkA in the nonphosphorylated and phosphorylated state with MptpA, (iv) dephosphorylation of PtkA by MptpA, and (v) PtkA phosphorylation by serine/threonine kinase ( Fig.…”

Section: Ptka Autophosphorylation and Regulation Of Its Catalytic Actmentioning

confidence: 99%

“…Biochemical analysis annotates PtkA as a member of the haloacid dehydrogenase-like hydrolase (HAD) superfamily, due to the presence of the active site motif D 85 XD, which is essential for the catalytic and autophosphorylation activity (18). Furthermore, PtkA acts as substrate for Mtb endogenous eukaryotic-like STPKs (20), which might represent an additional level of regulation of PtkA activity. MptpA and PtkA, even if they do not represent typical on/off switches of signal transduction (19), are part of the Mtb regulatory system and therefore important target candidates for anti-TB therapy.…”

mentioning

confidence: 99%

The domain architecture of PtkA, the first tyrosine kinase from Mycobacterium tuberculosis, differs from the conventional kinase architecture

Niesteruk

Jonker

Richter

et al. 2018

Journal of Biological Chemistry

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The discovery that MptpA (low-molecular-weight protein tyrosine phosphatase A) from () has an essential role for virulence has motivated research of tyrosine-specific phosphorylation in and other pathogenic bacteria. The phosphatase activity of MptpA is regulated via phosphorylation on Tyr and Tyr Thus far, only a single tyrosine-specific kinase, protein-tyrosine kinase A (PtkA), encoded by the gene has been identified within the genome. MptpA undergoes phosphorylation by PtkA. PtkA is an atypical bacterial tyrosine kinase, as its sequence differs from the sequence consensus within this family. The lack of structural information on PtkA hampers the detailed characterization of the MptpA-PtkA interaction. Here, using NMR spectroscopy, we provide a detailed structural characterization of the PtkA architecture and describe its intra- and intermolecular interactions with MptpA. We found that PtkA's domain architecture differs from the conventional kinase architecture and is composed of two domains, the N-terminal highly flexible intrinsically disordered domain (IDD) and the C-terminal rigid kinase core domain (KCD). The interaction between the two domains, together with the structural model of the complex proposed in this study, reveal that the IDD is unstructured and highly dynamic, allowing for a "fly-casting-like" mechanism of transient interactions with the rigid KCD This interaction modulates the accessibility of the KCD active site. In general, the structural and functional knowledge of PtkA gained in this study is crucial for understanding the MptpA-PtkA interactions, the catalytic mechanism, and the role of the kinase-phosphatase regulatory system in virulence.

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Phosphorylation of Mycobacterium tuberculosis protein tyrosine kinase A PtkA by Ser/Thr protein kinases

Cited by 16 publications

References 41 publications

Targeting the messengers: Serine/threonine protein kinases as potential targets for antimycobacterial drug development

Targeting the messengers: Serine/threonine protein kinases as potential targets for antimycobacterial drug development

Structural characterization of the intrinsically disordered domain of Mycobacterium tuberculosis protein tyrosine kinase A

The domain architecture of PtkA, the first tyrosine kinase from Mycobacterium tuberculosis, differs from the conventional kinase architecture

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