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A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems.

Zhang D, Iyer LM, Aravind L - Nucleic Acids Res. (2011)

Bottom Line: In eukaryotes it appears to have been recruited as an adaptor to regulate modification of proteins by ubiquitination or polyglutamylation.Similarly, another widespread immunity protein from these toxin systems, namely the suppressor of fused (SuFu) superfamily has been recruited for comparable roles in eukaryotes.In animal DNA viruses, such as herpesviruses, poxviruses, iridoviruses and adenoviruses, the ability of the SUKH domain to bind diverse targets has been deployed to counter diverse anti-viral responses by interacting with specific host proteins.

View Article: PubMed Central - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

ABSTRACT
The use of nucleases as toxins for defense, offense or addiction of selfish elements is widely encountered across all life forms. Using sensitive sequence profile analysis methods, we characterize a novel superfamily (the SUKH superfamily) that unites a diverse group of proteins including Smi1/Knr4, PGs2, FBXO3, SKIP16, Syd, herpesviral US22, IRS1 and TRS1, and their bacterial homologs. Using contextual analysis we present evidence that the bacterial members of this superfamily are potential immunity proteins for a variety of toxin systems that also include the recently characterized contact-dependent inhibition (CDI) systems of proteobacteria. By analyzing the toxin proteins encoded in the neighborhood of the SUKH superfamily we predict that they possess domains belonging to diverse nuclease and nucleic acid deaminase families. These include at least eight distinct types of DNases belonging to HNH/EndoVII- and restriction endonuclease-fold, and RNases of the EndoU-like and colicin E3-like cytotoxic RNases-folds. The N-terminal domains of these toxins indicate that they are extruded by several distinct secretory mechanisms such as the two-partner system (shared with the CDI systems) in proteobacteria, ESAT-6/WXG-like ATP-dependent secretory systems in Gram-positive bacteria and the conventional Sec-dependent system in several bacterial lineages. The hedgehog-intein domain might also release a subset of toxic nuclease domains through auto-proteolytic action. Unlike classical colicin-like nuclease toxins, the overwhelming majority of toxin systems with the SUKH superfamily is chromosomally encoded and appears to have diversified through a recombination process combining different C-terminal nuclease domains to N-terminal secretion-related domains. Across the bacterial superkingdom these systems might participate in discriminating `self' or kin from `non-self' or non-kin strains. Using structural analysis we demonstrate that the SUKH domain possesses a versatile scaffold that can be used to bind a wide range of protein partners. In eukaryotes it appears to have been recruited as an adaptor to regulate modification of proteins by ubiquitination or polyglutamylation. Similarly, another widespread immunity protein from these toxin systems, namely the suppressor of fused (SuFu) superfamily has been recruited for comparable roles in eukaryotes. In animal DNA viruses, such as herpesviruses, poxviruses, iridoviruses and adenoviruses, the ability of the SUKH domain to bind diverse targets has been deployed to counter diverse anti-viral responses by interacting with specific host proteins.

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Multiple sequence alignments and structural scaffolds of the distinct families of the HNH/EndoVII fold recovered in SUKH neighborhoods: HNH, NucA, WHH, LHH, AHH, DH-NNK and GH-E. Their secondary structures are indicated above the alignments (‘e’ in blue, β-sheet; ‘h’ in red, α-helix). The numbers in bracket are indicative of the excluded residues from sequences. ‘hash’ indicates the residues involved in metal ion-binding, ‘percent’ symbol indicates the conserved histidine which is required for activation of the water molecule for hydrolysis and ‘asterisk’ indicates the conserved asparagines. On the right, structures of HNH and EndoG families are shown as cartoon representations with the central structural core colored by structural element type (α-helices in purple, β-sheets in yellow), and key catalytic residues highlighted. For those newly identified families, inferred topology diagrams of their core nuclease domains are shown with conserved catalytic residues.
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Figure 3: Multiple sequence alignments and structural scaffolds of the distinct families of the HNH/EndoVII fold recovered in SUKH neighborhoods: HNH, NucA, WHH, LHH, AHH, DH-NNK and GH-E. Their secondary structures are indicated above the alignments (‘e’ in blue, β-sheet; ‘h’ in red, α-helix). The numbers in bracket are indicative of the excluded residues from sequences. ‘hash’ indicates the residues involved in metal ion-binding, ‘percent’ symbol indicates the conserved histidine which is required for activation of the water molecule for hydrolysis and ‘asterisk’ indicates the conserved asparagines. On the right, structures of HNH and EndoG families are shown as cartoon representations with the central structural core colored by structural element type (α-helices in purple, β-sheets in yellow), and key catalytic residues highlighted. For those newly identified families, inferred topology diagrams of their core nuclease domains are shown with conserved catalytic residues.

Mentions: Contextual information gleaned from gene neighborhoods in prokaryotes and domain architectures of proteins, when combined with sequence analysis, can be a powerful means of discerning protein function (47). Indeed, this method has proven particularly effective in both function prediction and identification of new analogous systems, using the organizational syntax of tightly linked genes, in case of toxin–antitoxin and restriction-modification systems (9,13,14,23,48). To better understand the role of the SUKH domain we performed a detailed analysis of the gene-neighborhoods of all bacterial genes encoding a protein with this domain (Figure 2). Consequently, we were able to identify at least three striking themes among the gene-neighborhoods of this superfamily. Firstly, across the bacterial phylogenetic tree we found numerous genomic neighborhoods that linked two or more adjacent genes encoding SUKH domain proteins. In certain cases, e.g. B. grahamii (gi: 240850988), we found tandem arrays with up to six paralogous SUKH superfamily genes (Figure 2). We found that in several instances these paralogous versions are not closely related and in certain cases adjacent paralogs might belong to completely different SUKH groups. For example, we found combinations of genes encoding proteins belonging to the Smi1-like (SUKH-1), Syd-like (SUKH-2), SUKH-3 and SUKH-4 groups in the same neighborhood in several bacteria such as B. cereus MM3 and various Streptomyces species (Figure 2). This observation suggested that there appears to be selective pressure for the diversification of the linked SUKH domain proteins encoded in a gene neighborhood either via sequence divergence, or independent assembly of neighborhoods from distantly related paralogs of different groups. This situation, wherein multiple paralogous genes are linked together as tandem arrays in a neighborhood, is relatively rare in bacteria (49). Given that products of genes linked in conserved gene-neighborhoods physically interact, it is possible that these paralogs interact to form a single complex (47). On the other hand, the multiple paralogs could also represent different alternative versions of the same component of a system which is under selection to display diversity. Given the great variability in the numbers and types of paralogous versions of the SUKH superfamily encoded by these neighborhoods, we favor the later explanation in this case (details see below). The second major feature that emerged from the analysis of gene neighborhoods was the linkage of genes encoding diverse SUKH superfamily members to genes encoding different types of nucleases (Figure 2). Among these, we observed multiple linkages in distantly related bacteria, such as B. thuringiensis and M. marina and S. griseoflavus, to genes for nucleases of the metal-dependent NucA family, which includes the well-studied S. marcescens secreted endonuclease (50) and the Anabaena non-specific endonuclease NucA, which degrades both RNA and DNA (51). Another prominent linkage observed in several bacteria, such as M.infernorum, various Bacillus species and N. mucosa, was to genes encoding proteins with a HNH superfamily nuclease domain (Figure 3). Sequence analysis showed that several of the HNH domains were related to similar nuclease domains found in previously studied bacteriocins such as pyocin AP41 of P. aeruginosa, Klebsiella klebicin B and colicin E8 of E. coli (52). These linkages involved members of both the Smi1-like and Syd-like groups; thus, despite their diversity, potential functional interactions with different types of nuclease domains are a common feature of the bacterial representatives of the SUKH superfamily.Figure 2.


A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems.

Zhang D, Iyer LM, Aravind L - Nucleic Acids Res. (2011)

Multiple sequence alignments and structural scaffolds of the distinct families of the HNH/EndoVII fold recovered in SUKH neighborhoods: HNH, NucA, WHH, LHH, AHH, DH-NNK and GH-E. Their secondary structures are indicated above the alignments (‘e’ in blue, β-sheet; ‘h’ in red, α-helix). The numbers in bracket are indicative of the excluded residues from sequences. ‘hash’ indicates the residues involved in metal ion-binding, ‘percent’ symbol indicates the conserved histidine which is required for activation of the water molecule for hydrolysis and ‘asterisk’ indicates the conserved asparagines. On the right, structures of HNH and EndoG families are shown as cartoon representations with the central structural core colored by structural element type (α-helices in purple, β-sheets in yellow), and key catalytic residues highlighted. For those newly identified families, inferred topology diagrams of their core nuclease domains are shown with conserved catalytic residues.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113570&req=5

Figure 3: Multiple sequence alignments and structural scaffolds of the distinct families of the HNH/EndoVII fold recovered in SUKH neighborhoods: HNH, NucA, WHH, LHH, AHH, DH-NNK and GH-E. Their secondary structures are indicated above the alignments (‘e’ in blue, β-sheet; ‘h’ in red, α-helix). The numbers in bracket are indicative of the excluded residues from sequences. ‘hash’ indicates the residues involved in metal ion-binding, ‘percent’ symbol indicates the conserved histidine which is required for activation of the water molecule for hydrolysis and ‘asterisk’ indicates the conserved asparagines. On the right, structures of HNH and EndoG families are shown as cartoon representations with the central structural core colored by structural element type (α-helices in purple, β-sheets in yellow), and key catalytic residues highlighted. For those newly identified families, inferred topology diagrams of their core nuclease domains are shown with conserved catalytic residues.
Mentions: Contextual information gleaned from gene neighborhoods in prokaryotes and domain architectures of proteins, when combined with sequence analysis, can be a powerful means of discerning protein function (47). Indeed, this method has proven particularly effective in both function prediction and identification of new analogous systems, using the organizational syntax of tightly linked genes, in case of toxin–antitoxin and restriction-modification systems (9,13,14,23,48). To better understand the role of the SUKH domain we performed a detailed analysis of the gene-neighborhoods of all bacterial genes encoding a protein with this domain (Figure 2). Consequently, we were able to identify at least three striking themes among the gene-neighborhoods of this superfamily. Firstly, across the bacterial phylogenetic tree we found numerous genomic neighborhoods that linked two or more adjacent genes encoding SUKH domain proteins. In certain cases, e.g. B. grahamii (gi: 240850988), we found tandem arrays with up to six paralogous SUKH superfamily genes (Figure 2). We found that in several instances these paralogous versions are not closely related and in certain cases adjacent paralogs might belong to completely different SUKH groups. For example, we found combinations of genes encoding proteins belonging to the Smi1-like (SUKH-1), Syd-like (SUKH-2), SUKH-3 and SUKH-4 groups in the same neighborhood in several bacteria such as B. cereus MM3 and various Streptomyces species (Figure 2). This observation suggested that there appears to be selective pressure for the diversification of the linked SUKH domain proteins encoded in a gene neighborhood either via sequence divergence, or independent assembly of neighborhoods from distantly related paralogs of different groups. This situation, wherein multiple paralogous genes are linked together as tandem arrays in a neighborhood, is relatively rare in bacteria (49). Given that products of genes linked in conserved gene-neighborhoods physically interact, it is possible that these paralogs interact to form a single complex (47). On the other hand, the multiple paralogs could also represent different alternative versions of the same component of a system which is under selection to display diversity. Given the great variability in the numbers and types of paralogous versions of the SUKH superfamily encoded by these neighborhoods, we favor the later explanation in this case (details see below). The second major feature that emerged from the analysis of gene neighborhoods was the linkage of genes encoding diverse SUKH superfamily members to genes encoding different types of nucleases (Figure 2). Among these, we observed multiple linkages in distantly related bacteria, such as B. thuringiensis and M. marina and S. griseoflavus, to genes for nucleases of the metal-dependent NucA family, which includes the well-studied S. marcescens secreted endonuclease (50) and the Anabaena non-specific endonuclease NucA, which degrades both RNA and DNA (51). Another prominent linkage observed in several bacteria, such as M.infernorum, various Bacillus species and N. mucosa, was to genes encoding proteins with a HNH superfamily nuclease domain (Figure 3). Sequence analysis showed that several of the HNH domains were related to similar nuclease domains found in previously studied bacteriocins such as pyocin AP41 of P. aeruginosa, Klebsiella klebicin B and colicin E8 of E. coli (52). These linkages involved members of both the Smi1-like and Syd-like groups; thus, despite their diversity, potential functional interactions with different types of nuclease domains are a common feature of the bacterial representatives of the SUKH superfamily.Figure 2.

Bottom Line: In eukaryotes it appears to have been recruited as an adaptor to regulate modification of proteins by ubiquitination or polyglutamylation.Similarly, another widespread immunity protein from these toxin systems, namely the suppressor of fused (SuFu) superfamily has been recruited for comparable roles in eukaryotes.In animal DNA viruses, such as herpesviruses, poxviruses, iridoviruses and adenoviruses, the ability of the SUKH domain to bind diverse targets has been deployed to counter diverse anti-viral responses by interacting with specific host proteins.

View Article: PubMed Central - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

ABSTRACT
The use of nucleases as toxins for defense, offense or addiction of selfish elements is widely encountered across all life forms. Using sensitive sequence profile analysis methods, we characterize a novel superfamily (the SUKH superfamily) that unites a diverse group of proteins including Smi1/Knr4, PGs2, FBXO3, SKIP16, Syd, herpesviral US22, IRS1 and TRS1, and their bacterial homologs. Using contextual analysis we present evidence that the bacterial members of this superfamily are potential immunity proteins for a variety of toxin systems that also include the recently characterized contact-dependent inhibition (CDI) systems of proteobacteria. By analyzing the toxin proteins encoded in the neighborhood of the SUKH superfamily we predict that they possess domains belonging to diverse nuclease and nucleic acid deaminase families. These include at least eight distinct types of DNases belonging to HNH/EndoVII- and restriction endonuclease-fold, and RNases of the EndoU-like and colicin E3-like cytotoxic RNases-folds. The N-terminal domains of these toxins indicate that they are extruded by several distinct secretory mechanisms such as the two-partner system (shared with the CDI systems) in proteobacteria, ESAT-6/WXG-like ATP-dependent secretory systems in Gram-positive bacteria and the conventional Sec-dependent system in several bacterial lineages. The hedgehog-intein domain might also release a subset of toxic nuclease domains through auto-proteolytic action. Unlike classical colicin-like nuclease toxins, the overwhelming majority of toxin systems with the SUKH superfamily is chromosomally encoded and appears to have diversified through a recombination process combining different C-terminal nuclease domains to N-terminal secretion-related domains. Across the bacterial superkingdom these systems might participate in discriminating `self' or kin from `non-self' or non-kin strains. Using structural analysis we demonstrate that the SUKH domain possesses a versatile scaffold that can be used to bind a wide range of protein partners. In eukaryotes it appears to have been recruited as an adaptor to regulate modification of proteins by ubiquitination or polyglutamylation. Similarly, another widespread immunity protein from these toxin systems, namely the suppressor of fused (SuFu) superfamily has been recruited for comparable roles in eukaryotes. In animal DNA viruses, such as herpesviruses, poxviruses, iridoviruses and adenoviruses, the ability of the SUKH domain to bind diverse targets has been deployed to counter diverse anti-viral responses by interacting with specific host proteins.

Show MeSH
Related in: MedlinePlus