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Host-pathogen o-methyltransferase similarity and its specific presence in highly virulent strains of Francisella tularensis suggests molecular mimicry.

Champion MD - PLoS ONE (2011)

Bottom Line: In highly clonal species that share the bulk of their genomes subtle changes in gene content and small-scale polymorphisms, especially those that may alter gene expression and protein-protein interactions, are more likely to have a significant effect on the pathogen's biology.Altogether, evidence suggests a role of the F. t. subsp. tularensis protein in a mechanism of molecular mimicry, similar perhaps to Legionella and Coxiella.These findings therefore provide insights into the evolution of niche-restriction and virulence in Francisella, and have broader implications regarding the molecular mechanisms that mediate host-pathogen relationships.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathogen Genomics, Translational Genomics Research Institute, Arizona, United States of America. mchampion@tgen.org

ABSTRACT
Whole genome comparative studies of many bacterial pathogens have shown an overall high similarity of gene content (>95%) between phylogenetically distinct subspecies. In highly clonal species that share the bulk of their genomes subtle changes in gene content and small-scale polymorphisms, especially those that may alter gene expression and protein-protein interactions, are more likely to have a significant effect on the pathogen's biology. In order to better understand molecular attributes that may mediate the adaptation of virulence in infectious bacteria, a comparative study was done to further analyze the evolution of a gene encoding an o-methyltransferase that was previously identified as a candidate virulence factor due to its conservation specifically in highly pathogenic Francisella tularensis subsp. tularensis strains. The o-methyltransferase gene is located in the genomic neighborhood of a known pathogenicity island and predicted site of rearrangement. Distinct o-methyltransferase subtypes are present in different Francisella tularensis subspecies. Related protein families were identified in several host species as well as species of pathogenic bacteria that are otherwise very distant phylogenetically from Francisella, including species of Mycobacterium. A conserved sequence motif profile is present in the mammalian host and pathogen protein sequences, and sites of non-synonymous variation conserved in Francisella subspecies specific o-methyltransferases map proximally to the predicted active site of the orthologous human protein structure. Altogether, evidence suggests a role of the F. t. subsp. tularensis protein in a mechanism of molecular mimicry, similar perhaps to Legionella and Coxiella. These findings therefore provide insights into the evolution of niche-restriction and virulence in Francisella, and have broader implications regarding the molecular mechanisms that mediate host-pathogen relationships.

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Motif conservation profiles and polymorphic sites map proximal to a 3-D region of the predicted o-methyltransferase active site.MEME motif regions are mapped against a Weblogo built with representative sequences (Figure 5). Non-synonymous polymorphisms in the o-methyltransferase protein identified in different subspecies of Francisella are indicated (*). The position relative to the human ortholog is given and cases where the amino acid is divergent between the Human and F.t. subspecies tularensis sequence is indicated below the motif. Key sites are spatially proximal to the o-methyltransferase active site (501 SAM) and in specific cases, mark the transition between a turn-coil region (123 ALA, 177 GLY). The labeled amino acid (223 PRO) is where the F.t. subspecies holarctica homolog truncates.
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pone-0020295-g006: Motif conservation profiles and polymorphic sites map proximal to a 3-D region of the predicted o-methyltransferase active site.MEME motif regions are mapped against a Weblogo built with representative sequences (Figure 5). Non-synonymous polymorphisms in the o-methyltransferase protein identified in different subspecies of Francisella are indicated (*). The position relative to the human ortholog is given and cases where the amino acid is divergent between the Human and F.t. subspecies tularensis sequence is indicated below the motif. Key sites are spatially proximal to the o-methyltransferase active site (501 SAM) and in specific cases, mark the transition between a turn-coil region (123 ALA, 177 GLY). The labeled amino acid (223 PRO) is where the F.t. subspecies holarctica homolog truncates.

Mentions: The effect of subspecies specific sequence differences on the predicted o-methyltransferase protein product was further analyzed using the JNet method to predict secondary structures based on the sequence profile of contiguous stretches of amino-acid sequence in the o-methyltransferase sequence alignments (Figure 3) [31]. A predicted structural profile of alternating α-helices and β-sheets characteristic of this family of conserved o-methyltransferases was identified in the predicted secondary structures of the Francisella Type A o-methyltransferase (EC 2.1.1.104) and highly conserved motif profiles were also identified (Figure 5). The solved structures for this family of Caffeoyl-CoA o-methyltransferases include two from plants, (1sui and 1sus), present in Medicago sativa (Alfalfa) and Mesembryanthemum crystallium. In both plant and human (PDB: 2AVD)(Figure 6), the protein consists of two distinct dimer subunits of approximately six β-sheets alternating with α-helices. Approximately three β-sheets denote a structural core region proximal to the active site of the protein.


Host-pathogen o-methyltransferase similarity and its specific presence in highly virulent strains of Francisella tularensis suggests molecular mimicry.

Champion MD - PLoS ONE (2011)

Motif conservation profiles and polymorphic sites map proximal to a 3-D region of the predicted o-methyltransferase active site.MEME motif regions are mapped against a Weblogo built with representative sequences (Figure 5). Non-synonymous polymorphisms in the o-methyltransferase protein identified in different subspecies of Francisella are indicated (*). The position relative to the human ortholog is given and cases where the amino acid is divergent between the Human and F.t. subspecies tularensis sequence is indicated below the motif. Key sites are spatially proximal to the o-methyltransferase active site (501 SAM) and in specific cases, mark the transition between a turn-coil region (123 ALA, 177 GLY). The labeled amino acid (223 PRO) is where the F.t. subspecies holarctica homolog truncates.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102702&req=5

pone-0020295-g006: Motif conservation profiles and polymorphic sites map proximal to a 3-D region of the predicted o-methyltransferase active site.MEME motif regions are mapped against a Weblogo built with representative sequences (Figure 5). Non-synonymous polymorphisms in the o-methyltransferase protein identified in different subspecies of Francisella are indicated (*). The position relative to the human ortholog is given and cases where the amino acid is divergent between the Human and F.t. subspecies tularensis sequence is indicated below the motif. Key sites are spatially proximal to the o-methyltransferase active site (501 SAM) and in specific cases, mark the transition between a turn-coil region (123 ALA, 177 GLY). The labeled amino acid (223 PRO) is where the F.t. subspecies holarctica homolog truncates.
Mentions: The effect of subspecies specific sequence differences on the predicted o-methyltransferase protein product was further analyzed using the JNet method to predict secondary structures based on the sequence profile of contiguous stretches of amino-acid sequence in the o-methyltransferase sequence alignments (Figure 3) [31]. A predicted structural profile of alternating α-helices and β-sheets characteristic of this family of conserved o-methyltransferases was identified in the predicted secondary structures of the Francisella Type A o-methyltransferase (EC 2.1.1.104) and highly conserved motif profiles were also identified (Figure 5). The solved structures for this family of Caffeoyl-CoA o-methyltransferases include two from plants, (1sui and 1sus), present in Medicago sativa (Alfalfa) and Mesembryanthemum crystallium. In both plant and human (PDB: 2AVD)(Figure 6), the protein consists of two distinct dimer subunits of approximately six β-sheets alternating with α-helices. Approximately three β-sheets denote a structural core region proximal to the active site of the protein.

Bottom Line: In highly clonal species that share the bulk of their genomes subtle changes in gene content and small-scale polymorphisms, especially those that may alter gene expression and protein-protein interactions, are more likely to have a significant effect on the pathogen's biology.Altogether, evidence suggests a role of the F. t. subsp. tularensis protein in a mechanism of molecular mimicry, similar perhaps to Legionella and Coxiella.These findings therefore provide insights into the evolution of niche-restriction and virulence in Francisella, and have broader implications regarding the molecular mechanisms that mediate host-pathogen relationships.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathogen Genomics, Translational Genomics Research Institute, Arizona, United States of America. mchampion@tgen.org

ABSTRACT
Whole genome comparative studies of many bacterial pathogens have shown an overall high similarity of gene content (>95%) between phylogenetically distinct subspecies. In highly clonal species that share the bulk of their genomes subtle changes in gene content and small-scale polymorphisms, especially those that may alter gene expression and protein-protein interactions, are more likely to have a significant effect on the pathogen's biology. In order to better understand molecular attributes that may mediate the adaptation of virulence in infectious bacteria, a comparative study was done to further analyze the evolution of a gene encoding an o-methyltransferase that was previously identified as a candidate virulence factor due to its conservation specifically in highly pathogenic Francisella tularensis subsp. tularensis strains. The o-methyltransferase gene is located in the genomic neighborhood of a known pathogenicity island and predicted site of rearrangement. Distinct o-methyltransferase subtypes are present in different Francisella tularensis subspecies. Related protein families were identified in several host species as well as species of pathogenic bacteria that are otherwise very distant phylogenetically from Francisella, including species of Mycobacterium. A conserved sequence motif profile is present in the mammalian host and pathogen protein sequences, and sites of non-synonymous variation conserved in Francisella subspecies specific o-methyltransferases map proximally to the predicted active site of the orthologous human protein structure. Altogether, evidence suggests a role of the F. t. subsp. tularensis protein in a mechanism of molecular mimicry, similar perhaps to Legionella and Coxiella. These findings therefore provide insights into the evolution of niche-restriction and virulence in Francisella, and have broader implications regarding the molecular mechanisms that mediate host-pathogen relationships.

Show MeSH
Related in: MedlinePlus