Overlapping Functionality of the Pht Proteins in Zinc Homeostasis of Streptococcus pneumoniae

Plumptre, Charles D.; Hughes, Catherine E.; Harvey, Richard M.; Eijkelkamp, Bart A.; McDevitt, Christopher A.; Paton, James C.

doi:10.1128/iai.02155-14

Cited by 38 publications

(48 citation statements)

References 24 publications

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“…Consistent with our previous observations, deletion of adcA in conjunction with phtA, phtB, and phtE (⌬adcA ⌬phtABE) resulted in a significant reduction in cellular Zn 2ϩ abundance relative to that for the wild type (P Ͻ 0.001) as determined by ICP-MS (Fig. 4A) (5). Although only minor, the additional deletion of phtD (⌬adcA ⌬phtABDE) resulted in a further reduction in Zn 2ϩ accumulation (15%; P Ͻ 0.05).…”

Section: Mutation Of the Ht Sites Results In Compromised Growth Under Znsupporting

confidence: 78%

“…In contrast, AdcA is capable of contributing to Zn 2ϩ acquisition independent of the Pht proteins, likely via its histidine-rich loop and C-terminal ZinT domain, features that are absent from AdcAII (4). Consistent with the high level of similarity between PhtA, PhtB, PhtD, and PhtE, each of the four Pht proteins has been shown to contribute to AdcAII-mediated Zn 2ϩ acquisition (5). Furthermore, deletion of the pht genes in an ⌬adcAII mutant reduced pneumococcal invasion relative to the parental ⌬adcAII strain, indicating that the Pht proteins hold roles in addition to AdcAII-mediated Zn 2ϩ acquisition (5).…”

mentioning

confidence: 61%

“…Consistent with the high level of similarity between PhtA, PhtB, PhtD, and PhtE, each of the four Pht proteins has been shown to contribute to AdcAII-mediated Zn 2ϩ acquisition (5). Furthermore, deletion of the pht genes in an ⌬adcAII mutant reduced pneumococcal invasion relative to the parental ⌬adcAII strain, indicating that the Pht proteins hold roles in addition to AdcAII-mediated Zn 2ϩ acquisition (5). Currently, it is not known whether these other functions are related to zinc homeostasis.…”

mentioning

confidence: 74%

“…The polyhistidine triad (Pht) family of proteins have also been shown to contribute to pneumococcal Zn 2ϩ acquisition (4)(5)(6). S. pneumoniae encodes four related Pht proteins, PhtA, PhtB, PhtD, and PhtE, which are thought to be predominantly anchored in the pneumococcal cell wall (7,8).…”

mentioning

confidence: 99%

“…The ability of the bacterium to import zinc (Zn 2ϩ ) ions from the extracellular environment is critical for its pathogenicity (2)(3)(4)(5). Pneumococcal Zn 2ϩ acquisition occurs via the cluster A-I substrate binding proteins (SBPs), AdcA and AdcAII, which deliver the metal ion to AdcCB, the ATP-binding cassette transporter, for cellular import (2)(3)(4).…”

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confidence: 99%

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The First Histidine Triad Motif of PhtD Is Critical for Zinc Homeostasis in Streptococcus pneumoniae

et al. 2016

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Streptococcus pneumoniae is the world's foremost human pathogen. Acquisition of the first row transition metal ion zinc is essential for pneumococcal colonization and disease. Zinc is acquired via the ATP-binding cassette transporter AdcCB and two zinc-binding proteins, AdcA and AdcAII. We have previously shown that AdcAII is reliant upon the polyhistidine triad (Pht) proteins to aid in zinc recruitment. Pht proteins generally contain five histidine (His) triad motifs that are believed to facilitate zinc binding and therefore play a significant role in pneumococcal metal ion homeostasis. However, the importance and potential redundancy of these motifs have not been addressed. We examined the effects of mutating each of the five His triad motifs of PhtD. The combination of in vitro growth assays, active zinc uptake, and PhtD expression studies show that the His triad closest to the protein's amino terminus is the most important for zinc acquisition. Intriguingly, in vivo competitive infection studies investigating the amino-and carboxyl-terminal His triad mutants indicate that the motifs have similar importance in colonization. Collectively, our new insights into the contributions of the individual His triad motifs of PhtD, and by extension the other Pht proteins, highlight the crucial role of the first His triad site in zinc acquisition. This study also suggests that the Pht proteins likely play a role beyond zinc acquisition in pneumococcal virulence.

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Section: Mutation Of the Ht Sites Results In Compromised Growth Under Znsupporting

confidence: 78%

mentioning

confidence: 61%

mentioning

confidence: 74%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The First Histidine Triad Motif of PhtD Is Critical for Zinc Homeostasis in Streptococcus pneumoniae

et al. 2016

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Pneumococcal lipoproteins involved in bacterial fitness, virulence, and immune evasion

et al. 2016

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Edited by Wilhelm JustStreptococcus pneumoniae (pneumococcus) has evolved sophisticated strategies to survive in several niches within the human body either as a harmless commensal or as a serious pathogen causing a variety of diseases. The dynamic interaction between pneumococci and resident host cells during colonization of the upper respiratory tract and at the site of infection is critical for bacterial survival and the development of disease. Pneumococcal lipoproteins are peripherally anchored membrane proteins and have pivotal roles in bacterial fitness including envelope stability, cell division, nutrient acquisition, signal transduction, transport (as substrate-binding proteins of ABC transporter systems), resistance to oxidative stress and antibiotics, and protein folding. In addition, lipoproteins are directly involved in virulence-associated processes such as adhesion, colonization, and persistence through immune evasion. Conversely, lipoproteins are also targets for the host response both as ligands for toll-like receptors and as targets for acquired antibodies. This review summarizes the multifaceted roles of selected pneumococcal lipoproteins and how this knowledge can be exploited to combat pneumococcal infections.

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Structural characterisation of the HT3 motif of the polyhistidine triad protein D from Streptococcus pneumoniae

et al. 2018

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The bacterium Streptococcus pneumoniae (the pneumococcus) is a major human pathogen that requires Zn for its survival and virulence in the host environment. Polyhistidine triad protein D (PhtD) has a known role in pneumococcal Zn homeostasis. However, the mechanistic basis of PhtD function remains unclear, partly due to a lack of structural information. Here, we determined the crystal structure of the fragment PhtD , containing the third Zn -binding histidine triad (HT) motif of the protein. Analysis of the structure suggests that Zn binding occurs at the surface of the protein and that all five HT motifs in the protein bind Zn and share similar structures. These new structural insights aid in our understanding of how the Pht proteins facilitate pneumococcal Zn acquisition.

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Overlapping Functionality of the Pht Proteins in Zinc Homeostasis of Streptococcus pneumoniae

Cited by 38 publications

References 24 publications

The First Histidine Triad Motif of PhtD Is Critical for Zinc Homeostasis in Streptococcus pneumoniae

The First Histidine Triad Motif of PhtD Is Critical for Zinc Homeostasis in Streptococcus pneumoniae

Pneumococcal lipoproteins involved in bacterial fitness, virulence, and immune evasion

Structural characterisation of the HT3 motif of the polyhistidine triad protein D from Streptococcus pneumoniae

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