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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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(A) Multiple sequence alignment of the different groups of the SUKH superfamily. The consensus was derived using the following amino acid classes: a, aromatic (FHWY, black on orange); b, big (EFHIKLMQRWY, black on light blue); h, hydrophobic (ACFGHILMTVWY, black on yellow); l, aliphatic (ILV, black on dark yellow); p, polar (CDEHKNQRST, blue on gray); s, small (ACDGNPSTV, black on blue); t, tiny (AGS, white on dark blue). Secondary structures derived from PDB structures or predicted using Jpred program are indicated above the alignment (‘e’ in blue, β-sheet; ‘h’ in red, α-helix). The numbers in bracket are indicative of the excluded residues from sequences. (B) Cartoons of known structures and a homology model of the US22 IRS-N domain made using Modeller are shown in approximately similar orientation. The α-helices are shown in purple, β-sheets in yellow, and loops in gray. Surface diagrams are colored based on their positions relative to the center of the structure (outside to inside: blue to red) to illustrate the cleft. (C) Domain architectures of representatives of the SUKH superfamily. Other than the domain abbreviations already provided in the text and the rest of the domains are the Ig-fold domain overlaps with PFAM DUF525; MoeA is a domain found in the MoeA protein of the molybdopterin biosynthesis pathway; U5, herpesvirus U5-like family (PF05999).
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Figure 1: (A) Multiple sequence alignment of the different groups of the SUKH superfamily. The consensus was derived using the following amino acid classes: a, aromatic (FHWY, black on orange); b, big (EFHIKLMQRWY, black on light blue); h, hydrophobic (ACFGHILMTVWY, black on yellow); l, aliphatic (ILV, black on dark yellow); p, polar (CDEHKNQRST, blue on gray); s, small (ACDGNPSTV, black on blue); t, tiny (AGS, white on dark blue). Secondary structures derived from PDB structures or predicted using Jpred program are indicated above the alignment (‘e’ in blue, β-sheet; ‘h’ in red, α-helix). The numbers in bracket are indicative of the excluded residues from sequences. (B) Cartoons of known structures and a homology model of the US22 IRS-N domain made using Modeller are shown in approximately similar orientation. The α-helices are shown in purple, β-sheets in yellow, and loops in gray. Surface diagrams are colored based on their positions relative to the center of the structure (outside to inside: blue to red) to illustrate the cleft. (C) Domain architectures of representatives of the SUKH superfamily. Other than the domain abbreviations already provided in the text and the rest of the domains are the Ig-fold domain overlaps with PFAM DUF525; MoeA is a domain found in the MoeA protein of the molybdopterin biosynthesis pathway; U5, herpesvirus U5-like family (PF05999).

Mentions: Despite the low average pairwise sequence similarity across this superfamily, all representatives are known or predicted to possess a similar core fold comprising of four conserved helices and six strands (Figure 1, Supplementary Data). Strands 1 and 2 form a β-hairpin and the strands 3–6 form a 4-stranded β-meander; however, the β-hairpin and the β-meander show only limited or no hydrogen-bonding along their length, despite being spatially beside each other. Thus, the structural core of the SUKH domain can be described as a split β-sheet with only weak interaction between its two parts. This structural peculiarity could potentially be critical for the functional interactions of the domain (see below). Based on sequence-similarity-based clustering and phylogenetic analysis five major groups can be recognized within the SUKH domain superfamily (Figure 1, Supplementary Data). The first of these, and the most widespread, is the one typified by Smi1/Knr4, FBXO3, SKIP16, PGs2 and YobK (that entirely includes the PFAM model PF09346, ‘SMI1/KNR4 family’, and additional proteins not detected by that model within it) and is seen in both bacteria and eukaryotes. This ensemble, which we term Smi1-like or SUKH-1 group includes the majority of the SUKH domains. We term the second group, prototyped by Syd, the Syd-like or SUKH-2 group. This group is largely restricted to the gammaproteobacteria and firmicutes. The SUKH-3 group prototyped by CA_C3700 (gi: 15896931) is widely distributed across most bacterial lineages. The group prototyped by SGR_4389 (gi: 182438182), the SUKH-4 group, is again seen in several bacteria and sporadically in fungi. The SUKH-5 or US22-like group is present in fowl adenoviruses, various vertebrate iridoviruses, archosaur poxviruses (Crocodilepox virus and Fowlpox virus), and in multiple copies in several herpesviruses (representatives of the alphaherpesvirus, betaherpesvirus and alloherpesvirus clades). Members of this group are also encoded by genomes of the early-branching chordate Branchiostoma, the salmon, the frog Rana catesbeiana and the duckbilled platypus, where they appear to have been acquired from the genomes of integrated herpesviruses (46). Phylogenetic analysis of each group, along with the phyletic patterns, strongly suggests that SUKH domain proteins have been widely disseminated both within and across the superkingdoms via extensive lateral transfer (Supplementary Data). In light of this pattern, the near complete absence of this superfamily in archaea suggests that there could be certain specific functional barriers that prevent acquisition of the SUKH domain by that superkingdom. Phylogenetic analysis strongly suggests that the groups SUKH-2–5 are monophyletic clades. The largest group, SUKH-1 is likely to represent the ancestral group from within which the above clades have diversified through rapid sequence divergence.Figure 1.


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)

(A) Multiple sequence alignment of the different groups of the SUKH superfamily. The consensus was derived using the following amino acid classes: a, aromatic (FHWY, black on orange); b, big (EFHIKLMQRWY, black on light blue); h, hydrophobic (ACFGHILMTVWY, black on yellow); l, aliphatic (ILV, black on dark yellow); p, polar (CDEHKNQRST, blue on gray); s, small (ACDGNPSTV, black on blue); t, tiny (AGS, white on dark blue). Secondary structures derived from PDB structures or predicted using Jpred program are indicated above the alignment (‘e’ in blue, β-sheet; ‘h’ in red, α-helix). The numbers in bracket are indicative of the excluded residues from sequences. (B) Cartoons of known structures and a homology model of the US22 IRS-N domain made using Modeller are shown in approximately similar orientation. The α-helices are shown in purple, β-sheets in yellow, and loops in gray. Surface diagrams are colored based on their positions relative to the center of the structure (outside to inside: blue to red) to illustrate the cleft. (C) Domain architectures of representatives of the SUKH superfamily. Other than the domain abbreviations already provided in the text and the rest of the domains are the Ig-fold domain overlaps with PFAM DUF525; MoeA is a domain found in the MoeA protein of the molybdopterin biosynthesis pathway; U5, herpesvirus U5-like family (PF05999).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: (A) Multiple sequence alignment of the different groups of the SUKH superfamily. The consensus was derived using the following amino acid classes: a, aromatic (FHWY, black on orange); b, big (EFHIKLMQRWY, black on light blue); h, hydrophobic (ACFGHILMTVWY, black on yellow); l, aliphatic (ILV, black on dark yellow); p, polar (CDEHKNQRST, blue on gray); s, small (ACDGNPSTV, black on blue); t, tiny (AGS, white on dark blue). Secondary structures derived from PDB structures or predicted using Jpred program are indicated above the alignment (‘e’ in blue, β-sheet; ‘h’ in red, α-helix). The numbers in bracket are indicative of the excluded residues from sequences. (B) Cartoons of known structures and a homology model of the US22 IRS-N domain made using Modeller are shown in approximately similar orientation. The α-helices are shown in purple, β-sheets in yellow, and loops in gray. Surface diagrams are colored based on their positions relative to the center of the structure (outside to inside: blue to red) to illustrate the cleft. (C) Domain architectures of representatives of the SUKH superfamily. Other than the domain abbreviations already provided in the text and the rest of the domains are the Ig-fold domain overlaps with PFAM DUF525; MoeA is a domain found in the MoeA protein of the molybdopterin biosynthesis pathway; U5, herpesvirus U5-like family (PF05999).
Mentions: Despite the low average pairwise sequence similarity across this superfamily, all representatives are known or predicted to possess a similar core fold comprising of four conserved helices and six strands (Figure 1, Supplementary Data). Strands 1 and 2 form a β-hairpin and the strands 3–6 form a 4-stranded β-meander; however, the β-hairpin and the β-meander show only limited or no hydrogen-bonding along their length, despite being spatially beside each other. Thus, the structural core of the SUKH domain can be described as a split β-sheet with only weak interaction between its two parts. This structural peculiarity could potentially be critical for the functional interactions of the domain (see below). Based on sequence-similarity-based clustering and phylogenetic analysis five major groups can be recognized within the SUKH domain superfamily (Figure 1, Supplementary Data). The first of these, and the most widespread, is the one typified by Smi1/Knr4, FBXO3, SKIP16, PGs2 and YobK (that entirely includes the PFAM model PF09346, ‘SMI1/KNR4 family’, and additional proteins not detected by that model within it) and is seen in both bacteria and eukaryotes. This ensemble, which we term Smi1-like or SUKH-1 group includes the majority of the SUKH domains. We term the second group, prototyped by Syd, the Syd-like or SUKH-2 group. This group is largely restricted to the gammaproteobacteria and firmicutes. The SUKH-3 group prototyped by CA_C3700 (gi: 15896931) is widely distributed across most bacterial lineages. The group prototyped by SGR_4389 (gi: 182438182), the SUKH-4 group, is again seen in several bacteria and sporadically in fungi. The SUKH-5 or US22-like group is present in fowl adenoviruses, various vertebrate iridoviruses, archosaur poxviruses (Crocodilepox virus and Fowlpox virus), and in multiple copies in several herpesviruses (representatives of the alphaherpesvirus, betaherpesvirus and alloherpesvirus clades). Members of this group are also encoded by genomes of the early-branching chordate Branchiostoma, the salmon, the frog Rana catesbeiana and the duckbilled platypus, where they appear to have been acquired from the genomes of integrated herpesviruses (46). Phylogenetic analysis of each group, along with the phyletic patterns, strongly suggests that SUKH domain proteins have been widely disseminated both within and across the superkingdoms via extensive lateral transfer (Supplementary Data). In light of this pattern, the near complete absence of this superfamily in archaea suggests that there could be certain specific functional barriers that prevent acquisition of the SUKH domain by that superkingdom. Phylogenetic analysis strongly suggests that the groups SUKH-2–5 are monophyletic clades. The largest group, SUKH-1 is likely to represent the ancestral group from within which the above clades have diversified through rapid sequence divergence.Figure 1.

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