Bacterial machineries for the assembly of membrane-embedded β-barrel proteins

Ranava, David; Caumont-Sarcos, Anne; Albenne, Cècile; Ieva, Raffaele

doi:10.1093/femsle/fny087

Cited by 38 publications

(39 citation statements)

References 158 publications

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“…They are synthesized as a precursor with a cleavable signal peptide and translocated to the periplasm by the Sec translocon. OMPs are then exported to the OM by the aid of periplasmic chaperones/foldases (7,8) and inserted into the OM by the function of the b-barrel assembly machinery (BAM) complex, the OMP translocon in the OM. The BAM complex is composed of 5 components; one β-barrel OMP (BamA) is associated with 4 lipoproteins (BamB-E) (8,9).…”

Section: Introductionmentioning

confidence: 99%

“…OMPs are then exported to the OM by the aid of periplasmic chaperones/foldases (7,8) and inserted into the OM by the function of the b-barrel assembly machinery (BAM) complex, the OMP translocon in the OM. The BAM complex is composed of 5 components; one β-barrel OMP (BamA) is associated with 4 lipoproteins (BamB-E) (8,9). This complex has a silk-hat (tophat) like structure wherein the β-barrel domain of BamA corresponds to the OM-embedded "crown" and the periplasmic "brim", which is supposed to undergo dynamic structural changes, is formed by the periplasmic POTRA domains of BamA and the lipoprotein components (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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Reversible auto-inhibitory regulation ofEscherichia colimetallopeptidase BepA for selective β-barrel protein degradation

Daimon

Narita

Miyazaki

et al. 2020

Preprint

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AbstractEscherichia coli periplasmic zinc-metallopeptidase BepA normally functions by promoting maturation of LptD, a β-barrel outer membrane protein involved in biogenesis of lipopolysaccharides, but degrades it when its membrane assembly is hampered. These processes should be properly regulated to ensure normal biogenesis of LptD, but the underlying mechanism of regulation, however, remains to be elucidated. A recently solved BepA structure has revealed unique features, in particular the active site is buried in the protease domain and conceivably inaccessible for substrate degradation. Additionally, the His-246 residue in the loop region containing helix α9 (α9/H246 loop), which has a potential flexibility and covers the active site, coordinates the zinc ion as the fourth ligand to exclude a catalytic water molecule, thereby suggesting that the crystal structure of BepA represents a latent form. To examine the roles of the α9/H246 loop in the regulation of the BepA activity, we constructed BepA mutants with a His-246 mutation or a deletion of the α9/H246 loop and analyzed their activities in vivo and in vitro. These mutants exhibited an elevated protease activity and, unlike the wild-type BepA, degraded LptD that is in the normal assembly pathway. In contrast, tethering of the α9/H246 loop repressed the LptD degradation, which suggests that the flexibility of this loop is important to the exhibition of the protease activity. Based on these results, we propose that the α9/H246 loop undergoes a reversible structural change that enables His-246-mediated switching (histidine switch) of its protease activity, which is important for regulated degradation of stalled/misassembled LptD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reversible auto-inhibitory regulation ofEscherichia colimetallopeptidase BepA for selective β-barrel protein degradation

Daimon

Narita

Miyazaki

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…The outer membrane of Gram-negative bacteria protects cells from external aggressions and mediates the secretion of virulence factors, and intact OMPs can promote host adhesion ( Henderson and Nataro, 2001 ; Ranava et al, 2018 ). Efficient and correct assembly of integral OMPs requires the TAM complex ( Heinz et al, 2015 ; Ranava et al, 2018 ). In Citrobacter rodentium , Salmonella enterica and E. coli , TAM mutation eliminated the virulence of the bacteria ( Selkrig et al, 2012 , 2014 ; Stubenrauch et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

The Translocation and Assembly Module (TAM) of Edwardsiella tarda Is Essential for Stress Resistance and Host Infection

Jia

Sun

et al. 2020

Front. Microbiol.

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Translocation and assembly module (TAM) is a protein channel known to mediate the secretion of virulence factors during pathogen infection. Edwardsiella tarda is a Gramnegative bacterium that is pathogenic to a wide range of farmed fish and other hosts including humans. In this study, we examined the function of the two components of the TAM, TamA and TamB, of E. tarda (named tamA Et and tamB Et , respectively). TamA Et was found to localize on the surface of E. tarda and be recognizable by TamA Et antibody. Compared to the wild type, the tamA and tamB knockouts, TX01 tamA and TX01 tamB, respectively, were significantly reduced in motility, flagella formation, invasion into host cells, intracellular replication, dissemination in host tissues, and inducing host mortality. The lost virulence capacities of TX01 tamA and TX01 tamB were restored by complementation with the tamA Et and tamB Et genes, respectively. Furthermore, TX01 tamA and TX01 tamB were significantly impaired in the ability to survive under low pH and oxidizing conditions, and were unable to maintain their internal pH balance and cellular structures in acidic environments, which led to increased susceptibility to lysozyme destruction. Taken together, these results indicate that TamA Et and TamB Et are essential for the virulence of E. tarda and required for E. tarda to survive under stress conditions.

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“…Both the IM and the OM harbor many anchored lipoproteins (Narita and Tokuda, 2017), as well as numerous integral membrane proteins. In the IM, these integral membrane proteins contain multiple transmembrane helical domains, whereas those in the OM, with one known exception, fold into transmembrane ß-barrel domains (Ranava et al, 2018). LPS is a complex glycolipid with many known structural variants, but with a common lipidated and phosphorylated bis-glucosamine core called lipid-A (Figure 1; Raetz et al, 2007).…”

Section: Outer Membrane Biogenesismentioning

confidence: 99%

Folded Synthetic Peptides and Other Molecules Targeting Outer Membrane Protein Complexes in Gram-Negative Bacteria

Robinson

2019

Front. Chem.

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Conformationally constrained peptidomimetics have been developed to mimic interfacial epitopes and target a wide selection of protein-protein interactions. ß-Hairpin mimetics based on constrained macrocyclic peptides have provided access to excellent structural mimics of ß-hairpin epitopes and found applications as interaction inhibitors in many areas of biology and medicinal chemistry. Recently, ß-hairpin peptidomimetics and naturally occurring ß-hairpin-shaped peptides have also been discovered with potent antimicrobial activity and novel mechanisms of action, targeting essential outer membrane protein (OMP) complexes in Gram-negative bacteria. This includes the Lpt complex, required for transporting LPS to the cell surface during OM biogenesis and the BAM complex that folds OMPs and inserts them into the OM bilayer. The Lpt complex is a macromolecular superstructure comprising seven different proteins (LptA-LptG) that spans the entire bacterial cell envelope, whereas the BAM complex is a folding machine comprising a ß-barrel OMP (BamA) and four different lipoproteins (BamB-BamE). Folded synthetic and natural ß-hairpin-shaped peptides appear well-suited for interacting with proteins within the Lpt and BAM complexes that are rich in ß-structure. Recent progress in identifying antibiotics targeting these complexes are reviewed here. Already a clinical candidate has been developed (murepavadin) that targets LptD, with potent antimicrobial activity specifically against pseudmonads. The ability of folded synthetic ß-hairpin epitope mimetics to interact with ß-barrel and ß-jellyroll domains in the Lpt and Bam complexes represent new avenues for antibiotic discovery, which may lead to the development of much needed new antimicrobials to combat the rise of drug-resistant pathogenic Gram-negative bacteria.

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Bacterial machineries for the assembly of membrane-embedded β-barrel proteins

Cited by 38 publications

References 158 publications

Reversible auto-inhibitory regulation ofEscherichia colimetallopeptidase BepA for selective β-barrel protein degradation

Reversible auto-inhibitory regulation ofEscherichia colimetallopeptidase BepA for selective β-barrel protein degradation

The Translocation and Assembly Module (TAM) of Edwardsiella tarda Is Essential for Stress Resistance and Host Infection

Folded Synthetic Peptides and Other Molecules Targeting Outer Membrane Protein Complexes in Gram-Negative Bacteria

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