Ring A of Nukacin ISK-1: A Lipid II-Binding Motif for Type-A(II) Lantibiotic

Islam, Mohammad Riazul; Nishie, Mami; Nagao, Jun Ichi; Zendo, Takeshi; Keller, Sandro; Nakayama, Jiro; Kohda, Daisuke; Sahl, Hans Georg; Sonomoto, Kenji

doi:10.1021/ja300007h

Cited by 63 publications

(67 citation statements)

References 26 publications

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“…The nonlantibiotic group contains peptides that do not require any modifications for their biological activity (11). In contrast, the lantibiotic groups contain peptides that require posttranslational modification for their antimicrobial activity (12,13). In lantibiotics, most of the serine and threonine residues are dehydrated to dehydroalanine (Dha) and dehydrobutyrine (Dhb), respectively, by modifying enzymes encoded within the lantibiotic synthesis operon.…”

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confidence: 99%

SmbFT, a Putative ABC Transporter Complex, Confers Protection against the Lantibiotic Smb in Streptococci

Biswas

2013

J Bacteriol

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Streptococcus mutans, a dental pathogen, secretes different kinds of lantibiotic and nonlantibiotic bacteriocins. For self-protection, a bacteriocin producer strain must possess one or more cognate immunity mechanisms. We report here the identification of one such immunity complex in S. mutans strain GS-5 that confers protection against Smb, a two-component lantibiotic. The immunity complex that we identified is an ABC transporter composed of two proteins: SmbF (the ATPase component) and SmbT (the permease component). Both of the protein-encoding genes are located within the smb locus. We show that GS-5 becomes sensitized to Smb upon deletion of smbT, which makes the ABC transporter nonfunctional. To establish the role SmbFT in providing immunity, we heterologously expressed this ABC transporter complex in four different sensitive streptococcal species and demonstrated that it can confer resistance against Smb. To explore the specificity of SmbFT in conferring resistance, we tested mutacin IV (a nonlantibiotic), nisin (a single peptide lantibiotics), and three peptide antibiotics (bacitracin, polymyxin B, and vancomycin). We found that SmbFT does not recognize these structurally different peptides. We then tested whether SmbFT can confer protection against haloduracin, another two-component lantibiotic that is structurally similar to Smb; SmbFT indeed conferred protection against haloduracin. SmbFT can also confer protection against an uncharacterized but structurally similar lantibiotic produced by Streptococcus gallolyticus. Our data suggest that SmbFT truly displays immunity function and confer protection against Smb and structurally similar lantibiotics.

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confidence: 99%

SmbFT, a Putative ABC Transporter Complex, Confers Protection against the Lantibiotic Smb in Streptococci

Biswas

2013

J Bacteriol

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“…Suicin has a ring A identical to that of bovicin HJ50, which contains a TxS/TxD/EC motif (the first x is in most cases a hydrophobic residue, the latter x is undefined) conserved among type AII lantibiotics (37). This motif has been shown to mediate binding of type AII lantibiotics to lipid II, an essential intermediate during peptidoglycan synthesis and subsequent cell wall formation (37). Therefore, further study is needed to elucidate whether suicin could display bactericidal activity by inhibiting cell wall synthesis.…”

Section: Discussionmentioning

confidence: 99%

Restoration of Bioactive Lantibiotic Suicin from a Remnant lan Locus of Pathogenic Streptococcus suis Serotype 2

Wang

Gao

Teng

et al. 2014

Appl Environ Microbiol

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cLantibiotics are ribosomally synthesized, posttranslationally modified antimicrobial peptides. Their biosynthesis genes are usually organized in gene clusters, which are mainly found in Gram-positive bacteria, including pathogenic streptococci. Three highly virulent Streptococcus suis serotype 2 strains (98HAH33, 05ZYH33, and SC84) have been shown to contain an 89K pathogenicity island. Here, on these islands, we unveiled and reannotated a putative lantibiotic locus designated sui which contains a virulence-associated two-component regulator, suiK-suiR. In silico analysis revealed that the putative lantibiotic modification gene suiM was interrupted by a 7.9-kb integron and that other biosynthesis-related genes contained various frameshift mutations. By reconstituting the intact suiM in Escherichia coli together with a semi-in vitro biosynthesis system, a putative lantibiotic named suicin was produced with bactericidal activities against a variety of Gram-positive strains, including pathogenic streptococci and vancomycin-resistant enterococci. Ring topology dissection indicated that the 34-amino-acid lantibiotic contained two methyllanthionine residues and one disulfide bridge, which render suicin in an N-terminal linear and C-terminal globular shape. To confirm the function of suiK-suiR, SuiR was overexpressed and purified. In vitro analysis showed that SuiR could specifically bind to the suiA gene promoter. Its coexpression with suiK could activate suiA gene promoter in Lactococcus lactis NZ9000. Conclusively, we obtained a novel lantibiotic suicin by restoring its production from the remnant sui locus and demonstrated that virulence-associated SuiK-SuiR regulates its production.

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“…Complex formation between LGN and Frmpd4 was measured by isothermal titration calorimetry (ITC) using a MicroCal VP-ITC calorimeter (MicroCal Inc.; Islam et al, 2012). Bacterially expressed wild-type (wt) MBP-Frmpd4-(978-1011) or a mutant protein with the L990A/Y1010A/ F1011A substitution was purified with Amylose Resin (New England Biolabs) followed by gel-filtration chromatography.…”

Section: Isothermal Titration Calorimetrymentioning

confidence: 99%

Structural basis for the recognition of the scaffold protein Frmpd4/Preso1 by the TPR domain of the adaptor protein LGN

2015

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The adaptor protein LGN interacts via the N-terminal domain comprising eight tetratricopeptide-repeat (TPR) motifs with its partner proteins mInsc, NuMA, Frmpd1 and Frmpd4 in a mutually exclusive manner. Here, the crystal structure of the LGN TPR domain in complex with human Frmpd4 is described at 1.5 Å resolution. In the complex, the LGN-binding region of Frmpd4 (amino-acid residues 990-1011) adopts an extended structure that runs antiparallel to LGN along the concave surface of the superhelix formed by the TPR motifs.Comparison with the previously determined structures of the LGN-Frmpd1, LGN-mInsc and LGN-NuMA complexes reveals that these partner proteins interact with LGN TPR1-6 via a common core binding region with consensus sequence (E/Q)XEX 4-5 (E/D/Q)X 1-2 (K/R)X 0-1 (V/I). In contrast to Frmpd1, Frmpd4 makes additional contacts with LGN via regions N-and C-terminal to the core sequence. The N-terminal extension is replaced by a specific -helix in mInsc, which drastically increases the direct contacts with LGN TPR7/8, consistent with the higher affinity of mInsc for LGN. A crystal structure of Frmpd4-bound LGN in an oxidized form is also reported, although oxidation does not appear to strongly affect the interaction with Frmpd4.

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Ring A of Nukacin ISK-1: A Lipid II-Binding Motif for Type-A(II) Lantibiotic

Cited by 63 publications

References 26 publications

SmbFT, a Putative ABC Transporter Complex, Confers Protection against the Lantibiotic Smb in Streptococci

SmbFT, a Putative ABC Transporter Complex, Confers Protection against the Lantibiotic Smb in Streptococci

Restoration of Bioactive Lantibiotic Suicin from a Remnant lan Locus of Pathogenic Streptococcus suis Serotype 2

Structural basis for the recognition of the scaffold protein Frmpd4/Preso1 by the TPR domain of the adaptor protein LGN

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