Conserved lipoproteins of pathogenic Neisseria species bearing the H.8 epitope: lipid-modified azurin and H.8 outer membrane protein

Cannon, Janne G.

doi:10.1128/cmr.2.suppl.s1

Cited by 38 publications

(33 citation statements)

References 30 publications

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“…This would be consistent with previous reports that electron donors to the NirK family of copper-containing nitrite reductases are either copper-containing azurins or c-type cytochromes (30). Although there is a lipid-associated azurin, Laz, in Neisseria, it has no role in nitrite reduction (21,31).…”

Section: Resultsmentioning

confidence: 99%

A Critical Role for the cccA Gene Product, Cytochrome c ₂ , in Diverting Electrons from Aerobic Respiration to Denitrification in Neisseria gonorrhoeae

2013

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Neisseria gonorrhoeae is a microaerophile that, when oxygen availability is limited, supplements aerobic respiration with a truncated denitrification pathway, nitrite reduction to nitrous oxide. We demonstrate that the cccA gene of Neisseria gonorrhoeae strain F62 (accession number NG0292) is expressed, but the product, cytochrome c 2 , accumulates to only low levels. Nevertheless, a cccA mutant reduced nitrite at about half the rate of the parent strain. We previously reported that cytochromes c 4 and c 5 transfer electrons to cytochrome oxidase cbb 3 by two independent pathways and that the CcoP subunit of cytochrome oxidase cbb 3 transfers electrons to nitrite. We show that mutants defective in either cytochrome c 4 or c 5 also reduce nitrite more slowly than the parent. By combining mutations in cccA (⌬c 2 ), cycA (⌬c 4 ), cycB (⌬c 5 ), and ccoP (ccoP-C368A), we demonstrate that cytochrome c 2 is required for electron transfer from cytochrome c 4 via the third heme group of CcoP to the nitrite reductase, AniA, and that cytochrome c 5 transfers electrons to nitrite reductase by an independent pathway. We propose that cytochrome c 2 forms a complex with cytochrome oxidase. If so, the redox state of cytochrome c 2 might regulate electron transfer to nitrite or oxygen. However, our data are more consistent with a mechanism in which cytochrome c 2 and the CcoQ subunit of cytochrome oxidase form alternative complexes that preferentially catalyze nitrite and oxygen reduction, respectively. Comparison with the much simpler electron transfer pathway for nitrite reduction in the meningococcus provides fascinating insights into niche adaptation within the pathogenic neisseriae.

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Section: Resultsmentioning

confidence: 99%

A Critical Role for the cccA Gene Product, Cytochrome c ₂ , in Diverting Electrons from Aerobic Respiration to Denitrification in Neisseria gonorrhoeae

2013

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“…1). 17 Similar to other bacterial outer membrane-bound lipoproteins, Laz includes a conserved 4-amino acid sequence termed lipobox [LVI][ASTVI][GAS]C at the N terminus. 19,20 The thiol group of the cysteine residue in the lipobox accepts diacylglycerol from phosphatidylglycerol through the action of transferase Lgt, and the resultant lipid-modified proteins are processed by signal peptidase II.…”

Section: Resultsmentioning

confidence: 99%

“…14 In addition to azurin, rusticyanin, another bacterial cupredoxin, causes apoptosis in human cancer cells. 16 Neisserial azurin-like protein, a "lipobox"-dependent lipid-modified azurin (Laz) bound to the outer membrane, 17 also enters brain tumors such as glioblastomas and exhibits significant toxicity against the cancer cells, 18 suggesting that Laz must cross the entry barrier to reach brain tumor cells. Laz includes a 39-amino acid residue region called the H.8 epitope at the N terminus prior to the azurin domain.…”

Section: Introductionmentioning

confidence: 99%

Structural studies on Laz, a promiscuous anticancer Neisserial protein

et al. 2015

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Azurin and Laz (lipidated azurin) are 2 bacterial proteins with anticancer, anti-viral and anti-parasitic activities. Azurin, isolated from the bacterium Pseudomonas aeruginosa, termed Paz, demonstrates anticancer activity against a range of cancers but not against brain tumors. In contrast, Laz is produced by members of Gonococci/Meningococci, including Neisseria meningitides which can cross the blood-brain barrier to infect brain meninges. It has been previously reported that Laz has an additional 39 amino acid moiety, called an H.8 epitope, in the N-terminal part of the azurin moiety that allows Laz to cross the entry barrier to brain tumors such as glioblastomas. Exactly, how the H.8 epitope helps the azurin moiety of Laz to cross the entry barriers to attack glioblastoma cells is unknown. In this paper, we describe the structural features of the H.8 moiety in Laz using X-ray crystallography and demonstrate that while the azurin moiety of Laz adopts a b-sandwich fold with 2 b-sheets arranged in the Greek key motif, the H.8 epitope was present as a disordered structure outside the Greek key motif. Structures of Paz and H.8 epitope-deficient Laz are well superimposed. The structural flexibility of the H.8 motif in Laz explains the extracellular location of Laz in Neisseria where it can bind the key components of brain tumor cells to disrupt their tight junctions and allow entry of Laz inside the tumors to exert cytotoxicity.

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“…The envF gene product is likely to be a lipoprotein on the basis of the presence of a consensus lipid attachment site. Since several known or predicted prokaryotic lipoproteins such as the Neisseria gonorrhoeae H.8 gene product (6), the TraT product of the E. coli F factor (36), the E. coli nlpD gene product (19), and the S. typhimurium prgH and prgK genes (35) have been associated with serum sensitivity or virulence, we examined the possibility that EnvF plays a role in Salmonella virulence. Inactivation of this gene has no affect on strain virulence; therefore, it is unlikely that EnvF is a major contributor to Salmonella pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Salmonella typhimurium pagC/pagD chromosomal region

et al. 1995

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The PhoP/PhoQ two-component system regulates Salmonella typhimurium genes that are essential to bacterial virulence and survival within macrophages. The best characterized of these PhoP-activated genes (pag) is pagC, which encodes a 188-amino-acid envelope protein (W. S. Pulkkinen and S. I. Miller, J. Bacteriol. 173:86-93, 1991). We here report the identification of four genes (pagD, envE, msgA, and envF) located 5 to pagC. Each gene is transcribed from its own promoter, two of which (msgA and pagD) were defined by primer extension analysis. Three of these genes (pagD, envE, and envF) are predicted to encode envelope proteins. The pagD gene is transcribed in a direction opposite from that of and adjacent to pagC and is positively regulated by PhoP/PhoQ. Transposon insertions within pagD and msgA attenuate bacterial virulence and survival within macrophages; however, deletion of pagD has no effect on virulence. The product of the envF gene is predicted to be a lipoprotein on the basis of the presence of a consensus lipid attachment site. The low G؉C content of these genes and the homology of msgA to Shigella plasmid DNA suggest that this region may have been acquired by horizontal transmission.

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Conserved lipoproteins of pathogenic Neisseria species bearing the H.8 epitope: lipid-modified azurin and H.8 outer membrane protein

Cited by 38 publications

References 30 publications

A Critical Role for the cccA Gene Product, Cytochrome c ₂ , in Diverting Electrons from Aerobic Respiration to Denitrification in Neisseria gonorrhoeae

A Critical Role for the cccA Gene Product, Cytochrome c ₂ , in Diverting Electrons from Aerobic Respiration to Denitrification in Neisseria gonorrhoeae

Structural studies on Laz, a promiscuous anticancer Neisserial protein

Characterization of the Salmonella typhimurium pagC/pagD chromosomal region

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Conserved lipoproteins of pathogenic Neisseria species bearing the H.8 epitope: lipid-modified azurin and H.8 outer membrane protein

Cited by 38 publications

References 30 publications

A Critical Role for the cccA Gene Product, Cytochrome c 2 , in Diverting Electrons from Aerobic Respiration to Denitrification in Neisseria gonorrhoeae

A Critical Role for the cccA Gene Product, Cytochrome c 2 , in Diverting Electrons from Aerobic Respiration to Denitrification in Neisseria gonorrhoeae

Structural studies on Laz, a promiscuous anticancer Neisserial protein

Characterization of the Salmonella typhimurium pagC/pagD chromosomal region

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Product

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A Critical Role for the cccA Gene Product, Cytochrome c ₂ , in Diverting Electrons from Aerobic Respiration to Denitrification in Neisseria gonorrhoeae

A Critical Role for the cccA Gene Product, Cytochrome c ₂ , in Diverting Electrons from Aerobic Respiration to Denitrification in Neisseria gonorrhoeae