The Extended Conformation of the 2.9-Å Crystal Structure of the Three-PASTA Domain of a Ser/Thr Kinase from the Human Pathogen Staphylococcus aureus

Paracuellos, Patricia; Ballandras, Allison; Robert, Xavier; Kahn, Richard; Hervé, Mireille; Mengin‐Lecreulx, Dominique; Cozzone, Alain J.; Duclos, B.; Gouet, Patrice

doi:10.1016/j.jmb.2010.10.012

Cited by 33 publications

(36 citation statements)

References 50 publications

(53 reference statements)

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“…Stp1 (N315-SA1062), encodes a manganese-dependent serine/threonine phosphatase, capable of dephosphorylating Stk1 [23], [34]. Stk1 is thought to be a membrane protein which possesses three extracellular PASTA domains (penicillin-binding protein and serine/threonine kinase associated domain) [44]. Stk1 or Stp1 have been shown to have a role in S. aureus virulence, cell wall metabolism and antibiotic resistance (for review see [25]).…”

Section: Discussionmentioning

confidence: 99%

“…One plausible hypothesis is that Stk1 senses some feature(s) of the cell wall assembly process via its PASTA domains and phosphorylates multiple downstream factors that coordinate proper assembly and quality control [44]. In the event of encounter with cell wall active drugs such as glycopeptides, Stk1 could conceivably signal damage and initiate a cascade of signalling events that permit survival in the face of drug stress.…”

Section: Discussionmentioning

confidence: 99%

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Whole Genome Sequencing and Complete Genetic Analysis Reveals Novel Pathways to Glycopeptide Resistance in Staphylococcus aureus

et al. 2011

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The precise mechanisms leading to the emergence of low-level glycopeptide resistance in Staphylococcus aureus are poorly understood. In this study, we used whole genome deep sequencing to detect differences between two isogenic strains: a parental strain and a stable derivative selected stepwise for survival on 4 µg/ml teicoplanin, but which grows at higher drug concentrations (MIC 8 µg/ml). We uncovered only three single nucleotide changes in the selected strain. Nonsense mutations occurred in stp1, encoding a serine/threonine phosphatase, and in yjbH, encoding a post-transcriptional negative regulator of the redox/thiol stress sensor and global transcriptional regulator, Spx. A missense mutation (G45R) occurred in the histidine kinase sensor of cell wall stress, VraS. Using genetic methods, all single, pairwise combinations, and a fully reconstructed triple mutant were evaluated for their contribution to low-level glycopeptide resistance. We found a synergistic cooperation between dual phospho-signalling systems and a subtle contribution from YjbH, suggesting the activation of oxidative stress defences via Spx. To our knowledge, this is the first genetic demonstration of multiple sensor and stress pathways contributing simultaneously to glycopeptide resistance development. The multifactorial nature of glycopeptide resistance in this strain suggests a complex reprogramming of cell physiology to survive in the face of drug challenge.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing and Complete Genetic Analysis Reveals Novel Pathways to Glycopeptide Resistance in Staphylococcus aureus

et al. 2011

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“…In Gram-positive bacteria, large quantities of PG fragments are released, because these bacteria have no system to recycle them (15,41). Homologs of Stk in other organisms are activated by PG fragments, which bind to the extracellular PASTA domain of this protein (50,51,61,81).…”

Section: Discussionmentioning

confidence: 99%

Serine/Threonine Protein Kinase Stk Is Required for Virulence, Stress Response, and Penicillin Tolerance in Streptococcus pyogenes

et al. 2011

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Genes encoding one or more Ser/Thr protein kinases have been identified recently in many bacteria, including one (stk) in the human pathogen Streptococcus pyogenes (group A streptococcus [GAS]). We report that in GAS, stk is required to produce disease in a murine myositis model of infection. Using microarray and quantitative reverse transcription-PCR (qRT-PCR) studies, we found that Stk activates genes for virulence factors, osmoregulation, metabolism of ␣-glucans, and fatty acid biosynthesis, as well as genes affecting cell wall synthesis. Confirming these transcription studies, we determined that the stk deletion mutant is more sensitive to osmotic stress and to penicillin than the wild type. We discuss several possible Stk phosphorylation targets that might explain Stk regulation of expression of specific operons and the possible role of Stk in resuscitation from quiescence.

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“…PASTA repeats were first observed in the crystal structure of Streptococcus pneumoniae PBP2X, where two approximately 70-residue-long repeats adopted a unique ␤ 3 ␣ structural topology (35). However, the PASTA repeats of M. tuberculosis PknB and its Staphylococcus aureus homolog adopt a linear organization (12,134) (Fig. 4A).…”

Section: Estks In Bacteriamentioning

confidence: 96%

Eukaryote-Like Serine/Threonine Kinases and Phosphatases in Bacteria

Pereira

Goss

Dworkin

2011

Microbiol Mol Biol Rev

322

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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The Extended Conformation of the 2.9-Å Crystal Structure of the Three-PASTA Domain of a Ser/Thr Kinase from the Human Pathogen Staphylococcus aureus

Cited by 33 publications

References 50 publications

Whole Genome Sequencing and Complete Genetic Analysis Reveals Novel Pathways to Glycopeptide Resistance in Staphylococcus aureus

Whole Genome Sequencing and Complete Genetic Analysis Reveals Novel Pathways to Glycopeptide Resistance in Staphylococcus aureus

Serine/Threonine Protein Kinase Stk Is Required for Virulence, Stress Response, and Penicillin Tolerance in Streptococcus pyogenes

Eukaryote-Like Serine/Threonine Kinases and Phosphatases in Bacteria

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