FtsW is a peptidoglycan polymerase that is activated by its cognate penicillin-binding protein

Taguchi, Atsushi; Welsh, Michael A.; Marmont, Lindsey S.; Lee, Wonsik; Kahne, Daniel; Bernhardt, Thomas G.; Walker, Suzanne

doi:10.1101/358663

Cited by 18 publications

(24 citation statements)

References 30 publications

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“…FtsW has been shown to form a ternary complex with PBP3 and PBP1b, and the lipid II binding activity of FtsW inhibits the polymerization of lipid II by PBP1b in the absence of PBP3, while the presence of PBP3 stimulates the release of lipid II from FtsW, and activates its polymerization by PBP1b (Leclercq et al, ). In addition, new evidence supports glycosyltransferase activity for FtsW (Taguchi et al, ). These observations raised the possibility that FtsW activity is needed to ensure MurJ localization.…”

Section: Resultsmentioning

confidence: 86%

“…FtsW has been shown to form a ternary Chromosomal mNG-(GGS) 2 -MurJ fusion was introduced into strains that harbor temperature sensitive, depletable or deleted division proteins (except that the mNG-(GGS)2-MurJ was expressed in ΔtolA and Δpal strains from plasmid pXL05, and mCherry-MurJ was expressed in ΔamiABC strain from plasmid pNM037 (Leclercq et al, 2017). In addition, new evidence supports glycosyltransferase activity for FtsW (Taguchi et al, 2018). These observations raised the possibility that FtsW activity is needed to ensure MurJ localization.…”

Section: Murj Midcell Localization Requires Ftsw Activitymentioning

confidence: 99%

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FtsW activity and lipid II synthesis are required for recruitment of MurJ to midcell during cell division in Escherichia coli

Liu

Meiresonne

Bouhss

et al. 2018

Molecular Microbiology

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Peptidoglycan (PG) is the unique cell shape-determining component of the bacterial envelope, and is a key target for antibiotics. PG synthesis requires the transmembrane movement of the precursor lipid II, and MurJ has been shown to provide this activity in Escherichia coli. However, how MurJ functions in vivo has not been reported. Here we show that MurJ localizes both in the lateral membrane and at midcell, and is recruited to midcell simultaneously with late-localizing divisome proteins and proteins MraY and MurG. MurJ septal localization is dependent on the presence of a complete and active divisome, lipid II synthesis and PBP3/FtsW activities. Inactivation of MurJ, either directly by mutation or through binding with MTSES, did not affect the midcell localization of MurJ. Our study visualizes MurJ localization in vivo and reveals a possible mechanism of MurJ recruitment during cell division.

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Section: Resultsmentioning

confidence: 86%

Section: Murj Midcell Localization Requires Ftsw Activitymentioning

confidence: 99%

FtsW activity and lipid II synthesis are required for recruitment of MurJ to midcell during cell division in Escherichia coli

Liu

Meiresonne

Bouhss

et al. 2018

Molecular Microbiology

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“…Interestingly, the essential function of PBP1 is not dependent on its transpeptidase activity, suggesting that this protein has a second function. While writing this manuscript, preprint data from the Walker laboratory demonstrated that S. aureus PBP1 stimulates the essential TG activity of FtsW, independently of its TP active site 12 , which could explain the essentiality of PBP1. This regulation of the activity of SEDS proteins and bPBPs may be essential to avoid the synthesis of uncrosslinked glycans 27 , which has been shown to lead to a toxic futile cycle of glycan synthesis and degradation in E. coli 28 .…”

Section: Ormentioning

confidence: 99%

“…Some bacteria also have monofunctional glycosyltransferases (MGTs), enzymes with a TG domain with homology to the TG domain of aPBPs 10 . More recently, RodA and FtsW, members of the shape, elongation, division and sporulation (SEDS) protein family, were also shown to have transglycosylase activity [11][12][13] .…”

mentioning

confidence: 99%

SEDS-bPBP pairs direct Lateral and Septal Peptidoglycan Synthesis in Staphylococcus aureus

Reichmann

Tavares

Saraiva

et al. 2019

Preprint

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Peptidoglycan (PGN) is the major component of the bacterial cell wall, a structure essential for the physical integrity and shape of the cell. Bacteria maintain cell shape by directing PGN incorporation to distinct regions of the cell, namely through the localisation of the late stage PGN synthesis proteins. These include two key protein families, SEDS transglycosylases and the bPBP transpeptidases, proposed to function in cognate pairs. Rod-shaped bacteria have two SEDS-bPBP pairs, involved in cell elongation and cell division. Here, we elucidate why coccoid bacteria, such as Staphylococcus aureus, also possess two SEDS-bPBP pairs. We determined that S. aureus RodA-PBP3 and FtsW-PBP1 likely constitute cognate pairs of interacting proteins. Lack of RodA-PBP3 decreased cell eccentricity due to deficient pre-septal PGN synthesis, whereas the depletion of FtsW-PBP1 arrested normal septal PGN incorporation. Although PBP1 is an essential protein, a mutant lacking PBP1 transpeptidase activity is viable, showing that this protein has a second function. We propose that the FtsW-PBP1 pair has a role in stabilising the divisome at midcell. In the absence of these proteins, the divisome appears as multiple rings/arcs that drive lateral PGN incorporation, leading to cell elongation. We conclude that RodA-PBP3 and FtsW-PBP1 mediate lateral and septal PGN incorporation, respectively, and that the activity of these pairs must be balanced in order to maintain coccoid morphology.Peptidoglycan (PGN) synthesis is an essential process that is both spatially and temporally regulated to ensure that the bacterial cell shape is maintained 1 . Rod-shaped bacteria elongate by synthesising PGN along the length of the cell in a process directed by the cytoskeletal protein MreB 2 . In Escherichia coli and Bacillus subtilis, this protein polymerises into short filaments that move processively around the cell diameter, and organise a multi-protein machinery, including PGN synthesis proteins, referred to as the elongasome or the Rod system 3-5 . Cell division is dependent on another cytoskeletal protein, FtsZ, which polymerises to form the Z-ring and recruits a multi-protein complex responsible for septum synthesis, known as the divisome 6,7 . This complex directs PGN incorporation to the midcell, resulting in inward PGN synthesis, and eventually bisects the mother cell, leading to daughter cell separation.Ovococci such as Streptococcus pneumoniae and Lactococcus lactis lack MreB, and FtsZ is proposed to coordinate both elongation and septation 8,9 . In these organisms PGN is

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“…FtsW, a RodA homolog and a key component of the divisome machinery, forms a complex with FtsI (PBP3), which has been shown to interact with PBP1b, FtsN and other proteins of the divisome 34 . The FtsW-PBP3 complex shares similar interacting regions with the RodA-PBP2 complex, and is the confirmed PG polymerase of the divisome 35 .…”

Section: Introductionmentioning

confidence: 61%

Crippling the bacterial cell wall molecular machinery

Williams

Wheeler

Deghmane

et al. 2019

Preprint

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34Lytic transglycosylases (LT) are redundant enzymes that play a critical role in 35 peptidoglycan (PG) recycling and metabolism. LT(s) role in cell wall-modifying 36 complexes and usefulness as antimicrobial drug targets remain elusive. We determined at 37 high-resolution a structure of the membrane-bound homolog of the soluble LT from 38 Neisseria species with a disordered active site helix (alpha helix 30). Alpha helix 30 is 39 crucial for binding PG during catalysis 1 . Here we show using an alpha helix 30 deletion 40 strain that LT (LtgA) determines the integrity of the cell wall, participates in cell division 41 and separation, and can be manipulated to impair the fitness of the human pathogen 42 Neisseria meningitidis during infection. Characterization of ltgA helix deleted strain 43 interactome identified glycan chain remodeling enzymes whose function appear to be 44 modulated by LTs. Targeting LTs can disrupt the PG machinery, which is fatal for the 45 bacterium, a new approach for antibiotic development. 46 47 65 alpha helices (α 28, 29, 30, 31, 32, 33, 34, 35, 36, 37), with a six-alpha-helix bundle (α 66 29, 30, 31, 32, 33, 34) constituting the core of the active site that firmly secures the 67 glycan chain ( Fig. 1a). 68 LTs utilize a single catalytic residue, either a glutamate or aspartate, which plays 69 the role of an acid and then that of a base 7-11 . In our recent study, active LtgA was 70 monitored for the first time in the crystalline state, and the residues involved in the 71 substrate and product formation steps were identified. Globally, conformational changes 72 occurred in three domains, the U, C and L domains, between native LtgA and LtgA 73 bound to the product 5 . Substantial conformational changes were observed in the active 74 site, for example, during the product formation step, the active site adopted a more open 75 conformation 5 . 76 Many Gram-negative bacteria have multiple and redundant LTs; for example, 77 Escherichia coli has eight (MltA, MltB, MltC, MltD, MltE, MltF, MltG and Slt70), and 78 4 Neisseria species encodes 5 (LtgA, LtgB, LtgC, LtgD, and LtgE), suggesting that LT 79 activity is vital to the life cycle of the cell 12 . Because the activity of LTs is redundant, the 80 loss of one or more LTs in E. coli leads to no observable growth defects. When genes for 81 6 LTs were deleted from E. coli, a mild chaining phenotype was observed 13 . However, 82 despite lack of strong observable phenotypic changes, it has been suggested that LTs may 83 have well-defined roles in the cell. For example, the deletion of ltgA and ltgD in 84 Neisseria gonorrhoeae eliminates the release of cytotoxic PG monomers suggesting the 85 activity of LtgA and LtgD are redundant. Moreover, LtgA primarily localizes at the 86 septum, indicating a role in the divisome machinery; whereas, LtgD is distributed along 87 the entire cell surface 14 . 88 The activities of LTs are known to be inhibited by β-hexosaminidase inhibitors 89 (for example, NAG-thiazoline); bulgecins A, B and C;...

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FtsW is a peptidoglycan polymerase that is activated by its cognate penicillin-binding protein

Cited by 18 publications

References 30 publications

FtsW activity and lipid II synthesis are required for recruitment of MurJ to midcell during cell division in Escherichia coli

FtsW activity and lipid II synthesis are required for recruitment of MurJ to midcell during cell division in Escherichia coli

SEDS-bPBP pairs direct Lateral and Septal Peptidoglycan Synthesis in Staphylococcus aureus

Crippling the bacterial cell wall molecular machinery

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