Bacterial Growth Mindset: Structural Plasticity in Defense Systems

In this issue of Structure, Bertelsen et al. determine the three-dimensional structures Haemophilus influenzae VapD toxin, a Cas-2 homolog, with and without its cognate neutralizing antitoxin, VapX, that together comprise toxin-antitoxin system. These reveal unique stoichiometry, two toxins neutralized simultaneously by one VapX antitoxin. The virulence-associated protein D, or VapD, is encoded throughout genomes bacteria. Within (TA) systems, functions as toxin whose activity held in check direct interactions (Bertelsen al., 2020Bertelsen M.B. Senissar M. Nielsen M.H. Bisiak F. Cunha M.V. Molinaro A.L. Daines D.A. Brodersen D.E. Structural Basis for Toxin Inhibition VapXD Toxin-Antitoxin System.Structure. 2021; 29 (this issue): 139-150Abstract Full Text PDF Scopus (4) Google Scholar). ribonucleases an attractive antibacterial target due to their widespread presence pathogens concern multiple examples promoting survival bacterial cells during infections. current work provides structural snapshots further objective raises additional intriguing questions on molecular regulation TA systems recognition role modulating virulence important pathogen, influenza (Ren 2012Ren D. Walker A.N. Toxin-antitoxin loci vapBC-1 vapXD contribute nontypeable influenzae.BMC Microbiol. 2012; 12: 263Crossref PubMed (54) Scholar), furthered intrigue into function relation conserved structure. A similar phenotypic advantage has been noted Helicobacter pylori infection (Kwon 2012Kwon A.R. Kim J.H. Park S.J. Lee K.Y. Min Y.H. Im H. I. B.J. biochemical characterization HP0315 from endoribonuclease activity.Nucleic Acids Res. 40: 4216-4228Crossref (38) This “growth mindset” appears, general, be mediated cleaving RNA, thus altering available pool transcripts temporarily stunting selected (Harms 2018Harms A. Mitarai N. Gerdes K. Toxins, Targets, Triggers: An Overview Biology.Mol. Cell. 2018; 70: 768-784Abstract (266) resulting re-growth then adapted new environment infection. cell results increased virulence. Canonically, antitoxin type II contains self-repressing DNA binding motif that, many cases, modulates strength repression molecules are bound unusual lacks versatile oligosaccharide-binding (OB)-like fold frequently found interact carbohydrates. Strikingly, find it able symmetrical homodimer induce asymmetry inducing conformational changes helical loops surrounding ribonuclease active site (Figure 1), stoichiometry among system Therefore, appears single repress steric occlusion site. highly aspartate 2); remains determined if dimer functionally sites, further, number cleavage events arise activated homodimeric form ring-shaped trimeric oligomer dimers, placement along periphery maximizes exposure 1). While basis unknown, stoichiometric mismatch prominent external display antitoxins clues canonical model does not apply.Figure 2Repurposing Conserved Folds Different Applications Bacterial Defense SystemsShow full captionVapD homologs Cas2 proteins used CRISPR-Cas adaptation step. Despite conservation catalytic residue, typically “molecular ruler” rather than enzyme adaptation, highlighting plasticity fold.View Large Image Figure ViewerDownload Hi-res image Download (PPT) fold. similarity each components presents enigmatic example evolution. homologous GhoS V system, well component machinery vapD gene exists “orphan” (i.e., other operon) (Ka 2018Ka Jang D.M. Han B.W. Bae E. Molecular organization II-A CRISPR module interaction Cas9 via Csn2.Nucleic 46: 9805-9815Crossref (12) Scholar; Kwon Wang 2012Wang X. Lord Cheng H.Y. Osbourne D.O. Hong S.H. Sanchez-Torres V. Quiroga C. Zheng Herrmann T. Peti W. al.A where mRNA GhoT cleaved GhoS.Nat. Chem. Biol. 8: 855-861Crossref (208) Intriguingly, identified ancestor step CRISPR-based immunity (Koonin Zhang, 2017Koonin E.V. Zhang Coupling programmed suicide prokaryotes: Life-or-death choices.BioEssays. 2017; 39: 1-9Crossref (50) However, instead serves ruler Cas1 nuclease functions. Legionella pneumophila protein, own right moonlight both CRISPR-independent ribonuclease, latter contributing after engulfment amoebal hosts (Gunderson 2015Gunderson F.F. Mallama C.A. Fairbairn S.G. Cianciotto N.P. Nuclease promotes intracellular host cells.Infect. Immun. 2015; 83: 1008-1018Crossref (31) appear utilize intrinsic VapD/Cas2-like modulate growth, demonstrating folds comprising these different prokaryotic defense systems. promote infection, regardless views provided confirm evolutionary provide greater insights how variations at impact formation oligomerization. Their studies capture freedom around limiting through hydrogen bond formation, stability substrate recognition. now tools tease out RNA potential specificity leading result survival. It also regulated There exciting future building work, clear impacts approaches understanding shared structure-function relationships between SystemBertelsen al.StructureOctober 22, 2020In BriefIn paper, present structure toxic pathogenic bacterium influenzae, which causes range diseases humans. authors demonstrate makes more virulent, inactivated Full-Text