Expression, purification and X-ray characterization of residues 18–230 from the pneumococcal histidine triad protein A (PhtA) from<i>Streptococcus pneumoniae</i>

Riboldi-Tunnicliffe, A.; Bent, Colin J.; Isaacs, Neil W.; Mitchell, Tim

doi:10.1107/s0907444904004573

Cited by 10 publications

(10 citation statements)

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“…The residues coordinating to this metal are His194, His197, His199, and Asp173 in a distorted tetrahedral coordination geometry. The Zn 2+ ions appear to originate from the production of recombinant protein in Escherichia coli due to the natural affinity of PhtA protein for these ions, and not from chemical reagents used in purification or crystallization [138]. This structure, however, fails to provide more hints to the functional properties of the PhtA molecule, as well as other Pht proteins, outside of the possibility outlined above.…”

Section: Sequence and Bioinformatics Analysismentioning

confidence: 92%

“…As such, close association of binding Zn 2+ ions with the His-triad repeat sequence is risky. Strongest evidence of support of such Zn 2+ ion binding possibility comes from structural studies of a short fragment of PhtA protein containing aa residues 166-220 of this 816 residue long molecule (in the R6 S. pneumoniae strain) [137,138]. This short fragment contains a stable Zn 2+ binding motif with a novel structure.…”

Section: Sequence and Bioinformatics Analysismentioning

confidence: 95%

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Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Jedrzejas¹

2007

Cell. Mol. Life Sci.

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Bacteria present a variety of molecules either on their surface or in a cell-free form. These molecules take part in numerous processes in the interactions with their host, with its tissues and other molecules. These molecules are essential to bacterial pathogenesis either during colonization or the spread/invasion stages, and most are virulence factors. This review is focused on such molecules using Streptococcus pneumoniae, a Gram-positive bacterium, as an example. Selected surface proteins are introduced, their structure described, and, whenever available, their mechanisms of function on an atomic level are explained. Such mechanisms for hyaluronate lyase, pneumococcal surface protein A, pneumolysin, histidine-triad and fibronectin-binding proteins are discussed. Elucidation of molecular mechanisms of virulence factors is essential for the understanding of bacteria and their functional properties. Structural biology appears pivotal for these studies, as structural and mechanistic insights facilitate rational approach to the development of new treatments.

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Section: Sequence and Bioinformatics Analysismentioning

confidence: 92%

Section: Sequence and Bioinformatics Analysismentioning

confidence: 95%

Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Jedrzejas¹

2007

Cell. Mol. Life Sci.

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“…The crystal structure of a PhtA protein fragment has revealed that the HTP domain forms a zinc-binding fold [27], [28]. The Zn 2+ binding ability of HTP proteins was indeed confirmed for HtpA and PhtD by independent groups [18], [29].…”

Section: Introductionmentioning

confidence: 90%

Insight into the Evolution of the Histidine Triad Protein (HTP) Family in Streptococcus

et al. 2013

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The Histidine Triad Proteins (HTPs), also known as Pht proteins in Streptococcus pneumoniae, constitute a family of surface-exposed proteins that exist in many pathogenic streptococcal species. Although many studies have revealed the importance of HTPs in streptococcal physiology and pathogenicity, little is known about their origin and evolution. In this study, after identifying all htp homologs from 105 streptococcal genomes representing 38 different species/subspecies, we analyzed their domain structures, positions in genome, and most importantly, their evolutionary histories. By further projecting this information onto the streptococcal phylogeny, we made several major findings. First, htp genes originated earlier than the Streptococcus genus and gene-loss events have occurred among three streptococcal groups, resulting in the absence of the htp gene in the Bovis, Mutans and Salivarius groups. Second, the copy number of htp genes in other groups of Streptococcus is variable, ranging from one to four functional copies. Third, both phylogenetic evidence and domain structure analyses support the division of two htp subfamilies, designated as htp I and htp II. Although present mainly in the pyogenic group and in Streptococcus suis, htp II members are distinct from htp I due to the presence of an additional leucine-rich-repeat domain at the C-terminus. Finally, htp genes exhibit a faster nucleotide substitution rate than do housekeeping genes. Specifically, the regions outside the HTP domains are under strong positive selection. This distinct evolutionary pattern likely helped Streptococcus to easily escape from recognition by host immunity.

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“…However, the locus encoding Lsp is unusual, in that it is located in an operon along with a gene encoding a surface protein of the histidine triad family (phtD, SPy_2006). The histidine triad proteins were first identified in S. pneumoniae, and structural studies of the signature "pneumococcal histidine triad" motif (HXXHXH) have revealed that this motif can bind zinc (68,69). A recent report (61) shows a role in S. pneumoniae for Pht proteins in inhibiting surface deposition of complement involving interaction with complement factor H. An interesting possibility is that PhtD may interact with Lsp to promote zinc scavenging or perhaps may serve as an extracellular zinc reservoir.…”

Section: Vol 77 2009 S Pyogenes Lsp Is Required For Zinc Homeostasmentioning

confidence: 99%

The Metal Homeostasis Protein, Lsp, of Streptococcus pyogenes Is Necessary for Acquisition of Zinc and Virulence

2009

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"Cluster 9" family lipoproteins function as ligand-binding subunits of ABC-type transporters in maintaining transition metal homeostasis and have been implicated in the virulence of several bacteria. While these proteins share high similarity, the specific metal that they recognize and whether their role in virulence directly involves metal homeostasis cannot be reliably predicted. We examined the cluster 9 protein Lsp of Streptococcus pyogenes and found that specific deletion of lsp produced mutants highly attenuated in a murine model of soft tissue infection. Under standard in vitro conditions, growth of the Lsp ؊ mutant was indistinguishable from that of the wild type, but growth was defective under zinc-limited conditions. The growth defect could be complemented by plasmids expressing wild-type Lsp but not Lsp engineered to lack its putative lipidation residue. Furthermore, Zn 2؉ but not Mn 2؉ rescued Lsp ؊ growth, implicating Zn 2؉ as the physiological ligand for Lsp. Mutation of residues in the putative Zn 2؉ -binding pocket generated variants both hypo-and hyperresistant to zinc starvation, and both mutant classes displayed attenuated virulence. Together, these data suggest that Lsp is a ligand-binding component of an ABC-type zinc permease and that perturbation of zinc homeostasis inhibits the ability of S. pyogenes to cause disease in a zinc-limited host milieu.Transition metals, including iron, zinc, manganese, nickel, and copper, participate in many structural and catalytic functions that are necessary to support the pathogenesis of bacterial infections. However, the ease with which these metals promote cellular electron trafficking also gives them potential to engage in destructive metal-based reactions (25, 59). Thus, a successful pathogen must evolve mechanisms to control the availability and distribution of individual metals within the bacterial cell while exposed to a dynamic host environment with profoundly fluctuating transition metal abundance (13,15,41,62).Evidence is emerging to suggest that the mechanisms by which Streptococcus pyogenes (group A streptococcus) interacts with transition metals play an important role in its ability to cause disease. This gram-positive bacterium is the causative agent of numerous diseases of soft tissue, ranging from selflimiting (e.g., pharyngitis) to destructive and life-threatening (e.g., necrotizing fasciitis), as well as serious postinfectious sequelae such as rheumatic fever and acute glomerulonephritis. A number of metal transporters of S. pyogenes have been characterized, and several of these have been shown to play roles in the virulence of streptococcal infection in various animal models (3,4,40,41,57,70). However, the full repertoire of metal transporters and regulatory elements that comprise the metalloregulatory network of S. pyogenes has not been characterized. In particular, the import and export proteins specific for each of the important transition metals have not been identified. Consequently, global understanding of S. pyogenes transition me...

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Expression, purification and X-ray characterization of residues 18–230 from the pneumococcal histidine triad protein A (PhtA) fromStreptococcus pneumoniae

Cited by 10 publications

References 10 publications

Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Insight into the Evolution of the Histidine Triad Protein (HTP) Family in Streptococcus

The Metal Homeostasis Protein, Lsp, of Streptococcus pyogenes Is Necessary for Acquisition of Zinc and Virulence

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