Structure and function of the complex formed by the tuberculosis virulence factors CFP-10 and ESAT-6

Renshaw, Philip S.; Lightbody, Kirsty L.; Veverka, Václav; Muskett, Frederick W.; Kelly, Geoff; Frenkiel, Thomas A.; Gordon, Stephen V.; Hewinson, R. Glyn; Burke, Bernard; Norman, Jim C.; Williamson, Richard A.; Carr, Mark D.

doi:10.1038/sj.emboj.7600732

Cited by 292 publications

(347 citation statements)

References 34 publications

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“…As expected, the conserved WXG motif ( Figure 2D, red inverted triangle) was identified in the centre of the sequence. Examination of the structure of esxA DX09 revealed a helical hairpin with the WXG motif localized between the two α-helices ( Figure 2E, red region), consistent with previous reports on the ESAT-6-like protein structure [21,36]. Protein secretion is critical for both pathogenic and nonpathogenic organisms to exploit nutrient resources within the host or specific niches and escape the immune system.…”

Section: Comparison Of Different Gene Clusters Encoding T7ss Between supporting

confidence: 73%

“…The small protein, ESAT-6, was initially identified as a virulence factor secreted by T7SS-ESX of M. tuberculosis [21]. These protein members were characterised by a central tryptophan-variableglycine (WXG) motif [36]. To determine whether esxA from S.iniae DX09 contains this motif, we compared the protein sequences between actinobacteria and firmicutes bacteria ( Figure 2C).…”

Section: Comparison Of Different Gene Clusters Encoding T7ss Between mentioning

confidence: 99%

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Comparative genome analysis of Streptococcus iniae DX09 reveals new insights into niche adaptation and competitive host colonisation ability

Liu¹,

Wang²,

Wang³

2017

Oncotarget

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Streptococcus iniae is a significant pathogen in a variety of marine and freshwater cultured fish species. Previous investigations on S. iniae have been limited to a single virulence gene or genome. However, different strains are associated with varying pathogenicity and niche adaptation properties. For comprehensive characterization of the genetic variations in S. iniae, whole-genome sequencing of S. iniae DX09 (isolated from diseased catfish) was performed and comparative genome analysis with eight S. iniae strains conducted to determine the virulence evolution patterns. Comparative analysis of all sequenced S. iniae revealed genome-genome variations, mainly in two plasticity zones, within genes encoding specific functions, such as the Ess/type VII secretion system and phosphoenolpyruvate-carbohydrate phosphotransferase system, reflecting adaptation to colonisation of specific host habitats. The plasticity zones analyzed in the S. iniae genome may be a paradigm rather than a unique combination of horizontal gene transfer and underlie the emergence of pathogenic Gram-positive bacteria.

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Section: Comparison Of Different Gene Clusters Encoding T7ss Between supporting

confidence: 73%

Section: Comparison Of Different Gene Clusters Encoding T7ss Between mentioning

confidence: 99%

Comparative genome analysis of Streptococcus iniae DX09 reveals new insights into niche adaptation and competitive host colonisation ability

Liu¹,

Wang²,

Wang³

2017

Oncotarget

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“…Both the PE/PPE and the CFP-10/ESAT-6 proteins form heterodimeric complexes that are composed of elongated bundles of α-helices (32,45). These structural similarities point to a functional and/or evolutionary link between these major mycobacterial protein families.…”

Section: Discussionmentioning

confidence: 99%

General secretion signal for the mycobacterial type VII secretion pathway

Daleke

Ummels

Bawono³

et al. 2012

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

183

224

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Mycobacterial pathogens use specialized type VII secretion (T7S) systems to transport crucial virulence factors across their unusual cell envelope into infected host cells. These virulence factors lack classical secretion signals and the mechanism of substrate recognition is not well understood. Here we demonstrate that the model T7S substrates PE25/PPE41, which form a heterodimer, are targeted to the T7S pathway ESX-5 by a signal located in the C terminus of PE25. Site-directed mutagenesis of residues within this C terminus resulted in the identification of a highly conserved motif, i.e., YxxxD/E, which is required for secretion. This motif was also essential for the secretion of LipY, another ESX-5 substrate. Pathogenic mycobacteria have several different T7S systems and we identified a PE protein that is secreted by the ESX-1 system, which allowed us to compare substrate recognition of these two T7S systems. Surprisingly, this ESX-1 substrate contained a C-terminal signal functionally equivalent to that of PE25. Exchange of these C-terminal secretion signals between the PE proteins restored secretion, but each PE protein remained secreted via its own ESX secretion system, indicating that an additional signal(s) provides system specificity. Remarkably, the YxxxD/E motif was also present in and required for efficient secretion of the ESX-1 substrates CFP-10 and EspB. Therefore, our data show that the YxxxD/E motif is a general secretion signal that is present in all known mycobacterial T7S substrates or substrate complexes.

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“…The C-terminally His-tagged MtbESAT-6 was over-expressed as insoluble aggregates in E. coli inclusion bodies, comprising nearly 1/3 of the total protein. In previous reports (17,18,25), purification of the recombinant MtbESAT-6 protein was accomplished by extracting the protein aggregates from inclusion bodies with 8 M urea or 6 M guanidine, followed by an overnight dialysis in a refolding buffer. A C-terminal truncation of the purified MtbESAT-6 after overnight dialysis has been observed.…”

Section: Resultsmentioning

confidence: 99%

Mycobacterium tuberculosis ESAT-6 Exhibits a Unique Membrane-interacting Activity That Is Not Found in Its Ortholog from Non-pathogenic Mycobacterium smegmatis

Leon

Jiang

et al. 2012

Journal of Biological Chemistry

111

177

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Background: Mycobacterium tuberculosis ESAT-6 (MtbESAT-6) is required for phagosomal rupture and bacterial cytosolic translocation.Results: MtbESAT-6 underwent a pH-dependent conformational change and induced leakage of membrane vesicles, while its ortholog from non-pathogenic Mycobacterium smegmatis, MsESAT-6, did not. Conclusion: MtbESAT-6 possesses a unique membrane-interacting activity that is not found in MsESAT-6. Significance: This study links membrane-interacting activity of ESAT-6 to virulence of M. tuberculosis.

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Structure and function of the complex formed by the tuberculosis virulence factors CFP-10 and ESAT-6

Cited by 292 publications

References 34 publications

Comparative genome analysis of Streptococcus iniae DX09 reveals new insights into niche adaptation and competitive host colonisation ability

Comparative genome analysis of Streptococcus iniae DX09 reveals new insights into niche adaptation and competitive host colonisation ability

General secretion signal for the mycobacterial type VII secretion pathway

Mycobacterium tuberculosis ESAT-6 Exhibits a Unique Membrane-interacting Activity That Is Not Found in Its Ortholog from Non-pathogenic Mycobacterium smegmatis

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