The effect of HAMP domains on class IIIb adenylyl cyclases from <i>Mycobacterium tuberculosis</i>

Linder, Jürgen; Hammer, Arne; Schultz, Joachim E.

doi:10.1111/j.1432-1033.2004.04172.x

Cited by 44 publications

(47 citation statements)

References 24 publications

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“…The activities of the membrane-bound Rv3645 AC, the soluble HAMP-CHD complex, and the soluble cyclase catalytic domain are similar to those of the chimeras used here. Actually Rv3645 AC activity is affected by structural modifications of its own HAMP and the Rv3645 HAMP itself propagates the serine signal of Tsr in respective hybrid constructs (17,(21)(22). Our chimeras are similar to functional hybrid histidine kinases, e.g.…”

Section: Resultsmentioning

confidence: 89%

HAMP Domain-mediated Signal Transduction Probed with a Mycobacterial Adenylyl Cyclase as a Reporter

Mondéjar

Lupas

Schultz

et al. 2012

Journal of Biological Chemistry

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Background: HAMP domains accept signals from membrane receptors and propagate them possibly via rotation. Results: Using targeted mutations based on bioinformatics, sequence comparisons, and structures, we characterize the role of particular amino acids in signaling. Conclusion: Results are compatible with a gearbox model of HAMP rotation. Significance: Various models of HAMP domain-mediated signaling are testable.

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Section: Resultsmentioning

confidence: 89%

HAMP Domain-mediated Signal Transduction Probed with a Mycobacterial Adenylyl Cyclase as a Reporter

Mondéjar

Lupas

Schultz

et al. 2012

Journal of Biological Chemistry

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“…Other domains found within the putative adenylate cyclases of L. pneumophila are also commonly associated with this group of enzymes. HAMP domains (so designated for their presence in histidine kinases, adenylate cyclases, methyl binding proteins, and phosphatases), present in ladC and lpp1277, comprise a conserved region of approximately 50 amino acids that forms an ␣-helical region with the ability to regulate activity (27). The CHASE2 (defined as cyclases/histidine kinases associated sensory extracellular) domain, conserved in lpp1704, is an extracellular sensory domain that in Myxococcus xanthus participates in signal transduction during osmotic stress (23,56).…”

Section: Resultsmentioning

confidence: 99%

Significant Role for ladC in Initiation of Legionella pneumophila Infection

et al. 2008

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Previously, we identified ladC in a cohort of genes that were present in Legionella pneumophila but absent in other Legionella species. Here we constructed a ladC mutant of L. pneumophila and assessed its ability to replicate in mammalian cell lines and Acanthamoeba castellanii. The ladC mutant was recovered in significantly lower numbers than wild-type L. pneumophila at early time points, which was reversed upon transcomplementation with ladC but not ladC N430A/R434A , encoding a putative catalytically inactive derivative of the protein. In fact, complementation of ladC::Km with ladC N430A/R434A resulted in a severe replication defect within human and amoeba cell models of infection, which did not follow a typical dominant negative phenotype. Using differential immunofluorescence staining to distinguish adherent from intracellular bacteria, we found that the ladC mutant exhibited a 10-fold reduction in adherence to THP-1 macrophages but no difference in uptake by THP-1 cells. When tested in vivo in A/J mice, the competitive index of the ladC mutant dropped fivefold over 72 h, indicating a significant attenuation compared to wild-type L. pneumophila. Although localization of LadC to the bacterial inner membrane suggested that the protein may be involved in signaling pathways that regulate virulence gene expression, microarray analysis indicated that ladC does not influence the transcriptional profile of L. pneumophila in vitro or during A. castellanii infection. Although the mechanism by which LadC modulates the initial interaction between the bacterium and host cell remains unclear, we have established that LadC plays an important role in L. pneumophila infection.

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“…Both the number and diversity of functional ACs in M. tuberculosis are extraordinary compared with other microorganisms (27,35), and we think it likely that each cyclase is associated with a distinct signaling pathway. An exciting future challenge will be to determine how M. tuberculosis maintains discrete regulatory circuits using a single signal molecule and such a large number of ACs.…”

Section: Overview Of the Camp-regulated Network Of Genes In Bcgmentioning

confidence: 92%

“…Two of these genes (Rv1625c and Rv2435c) belong to the mammalian type adenylyl cyclase grouping, and both enzymes are active (19,28,35,50,54). Functionality has also been shown for the mycobacterial cyclases Rv1264, Rv1318c, Rv1319c, Rv1320c, and Rv3645 (6,27).…”

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confidence: 98%

Identification of Cyclic AMP-Regulated Genes in Mycobacterium tuberculosis Complex Bacteria under Low-Oxygen Conditions

Gazdik

McDonough

2005

J Bacteriol

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Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), which kills approximately 2 million people a year despite current treatment options. A greater understanding of the biology of this bacterium is needed to better combat TB disease. The M. tuberculosis genome encodes as many as 15 adenylate cyclases, suggesting that cyclic AMP (cAMP) has an important, yet overlooked, role in mycobacteria. This study examined the effect of exogenous cAMP on protein expression in Mycobacterium bovis BCG grown under hypoxic versus ambient conditions. Both shaking and shallow standing cultures were examined for each atmospheric condition. Different cAMP-dependent changes in protein expression were observed in each condition by two-dimensional gel electrophoresis. Shaking low-oxygen cultures produced the most changes (12), while standing ambient conditions showed the fewest (2). Five upregulated proteins, Rv1265, Rv2971, GroEL2, PE_PGRS6a, and malate dehydrogenase, were identified from BCG by mass spectrometry and were shown to also be regulated by cAMP at the mRNA level in both M. tuberculosis H37Rv and BCG. To our knowledge, these data provide the first direct evidence for cAMP-mediated gene regulation in TB complex mycobacteria.Tuberculosis (TB) is a leading cause of human death by an infectious agent, killing approximately 2 million people each year. Nearly one-third of the world's population is latently infected with the Mycobacterium tuberculosis bacillus, and 7 to 8 million new TB cases occur annually (49). A deadly synergy with the human immunodeficiency virus epidemic and an increasing proportion of drug-resistant cases contribute to TB's recent resurgence and complicate its treatment (7, 9). A better understanding of M. tuberculosis biology is needed to devise more effective treatments against TB. Gene regulation is critical for the interaction of the tubercle bacilli with their

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The effect of HAMP domains on class IIIb adenylyl cyclases from Mycobacterium tuberculosis

Cited by 44 publications

References 24 publications

HAMP Domain-mediated Signal Transduction Probed with a Mycobacterial Adenylyl Cyclase as a Reporter

HAMP Domain-mediated Signal Transduction Probed with a Mycobacterial Adenylyl Cyclase as a Reporter

Significant Role for ladC in Initiation of Legionella pneumophila Infection

Identification of Cyclic AMP-Regulated Genes in Mycobacterium tuberculosis Complex Bacteria under Low-Oxygen Conditions

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