An Updated Model of the Divisome: Regulation of the Septal Peptidoglycan Synthesis Machinery by the Divisome

Attaibi, Mohamed; Blaauwen, Tanneke den

doi:10.3390/ijms23073537

Cited by 25 publications

(29 citation statements)

References 127 publications

(302 reference statements)

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“…Blaauwen proposed a different model for the control of septal PG synthesis also based on a higher oligomeric state for the complex (49). Their model also considers FtsK, which exists in a hexameric state and binds to FtsQ (57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

A model of the interactions between the FtsQLB and the FtsWI peptidoglycan synthase complex in bacterial cell division

Craven

Condon

Senes

2022

Preprint

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In Escherichia coli, an important step in the divisome assembly pathway is the recruitment of the essential cell wall synthase complex FtsWI to the division site through interactions with the regulatory FtsQLB complex. Here, we investigate a key aspect of this recruitment by characterizing the structural organization of the FtsL-FtsW interaction. Mutations in the cytoplasmic and transmembrane regions of the two proteins result in cell division defects and loss of FtsW localization to division sites. We use these in vivo results to help validate the predicted interfaces from an AlphaFold2 model for the entire FtsQLBWI complex. Given the consistency between the predicted FtsQLBWI model and our current understanding of the structure and function of the complex, we further remodeled it, seeking insight into the potential structural transitions that may lead to activation of the FtsWI complex and PG synthesis. The model suggests that FtsLB serves as a support for FtsI, placing its periplasmic domain in an extended and possibly active conformation but it is also compatible with a proposed compact and possibly inactive conformation. Additionally, we reconfigure the model into an Fts[QLBWI]2 diprotomeric state, which suggests that FtsLB may act as a central hub during assembly of the PG synthesis machinery. Finally, we propose a possible role for FtsQ in activation of this machinery, potentially by acting as a gatekeeper for the interaction between the FtsL AWI region and FtsI. We propose that this gatekeeping function depends on a hinge next to the FtsLB CCD region, which has implications for the mechanisms behind the FtsLB off/on transition that is central to cell division regulation.

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Section: Discussionmentioning

confidence: 99%

A model of the interactions between the FtsQLB and the FtsWI peptidoglycan synthase complex in bacterial cell division

Craven

Condon

Senes

2022

Preprint

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“…Central to cell division is the divisome, , a dynamic complex composed of numerous membrane-associated proteins that assemble at the midcell plane to regulate cell constriction, peptidoglycan synthesis, and cell separation. Divisome assembly involves sequential and precisely orchestrated protein–protein interactions (PPI) with imbalances ultimately leading to cell death . In Gram-negative bacteria, efforts to target the divisome have focused on the inhibition of FtsZ polymerization in the cytoplasm, which represents one of the initial steps of bacterial cell division (Figure a), however, without providing potent inhibitors. − Consequently, the validation of alternative divisome targets is needed to further explore the potential of divisome inhibition in Gram-negative bacteria.…”

Section: Introductionmentioning

confidence: 99%

“…FtsK is recruited to assist in chromosome segregation and in turn recruits the FtsQBL complex, which serves as a structural hub for recruitment of late assembly proteins (dark gray). Interaction of FtsN with the FtsQBL complex indicates the completion of divisome complex formation. , (b) Crystal structure (PDB: 6h9o) of periplasmic FtsQ domains (white) in a complex with FtsB-derived peptide 24 (blue). FtsB residues essential for binding are shown in a stick representation .…”

Section: Introductionmentioning

confidence: 99%

Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

et al. 2022

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The use of antibiotics is threatened by the emergence and spread of multidrug-resistant strains of bacteria. Thus, there is a need to develop antibiotics that address new targets. In this respect, the bacterial divisome, a multi-protein complex central to cell division, represents a potentially attractive target. Of particular interest is the FtsQB subcomplex that plays a decisive role in divisome assembly and peptidoglycan biogenesis in E. coli . Here, we report the structure-based design of a macrocyclic covalent inhibitor derived from a periplasmic region of FtsB that mediates its binding to FtsQ. The bioactive conformation of this motif was stabilized by a customized cross-link resulting in a tertiary structure mimetic with increased affinity for FtsQ. To increase activity, a covalent handle was incorporated, providing an inhibitor that impedes the interaction between FtsQ and FtsB irreversibly. The covalent inhibitor reduced the growth of an outer membrane-permeable E. coli strain, concurrent with the expected loss of FtsB localization, and also affected the infection of zebrafish larvae by a clinical E. coli strain. This first-in-class inhibitor of a divisome protein–protein interaction highlights the potential of proteomimetic molecules as inhibitors of challenging targets. In particular, the covalent mode-of-action can serve as an inspiration for future antibiotics that target protein–protein interactions.

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“…A recent review synthesized evidence to date and used structure predictions to propose a model of allosteric regulation of FtsWI, in which multiple interactions cooperatively stabilize an active conformation 21 . This work drew on structure predictions of complexes FtsWI, FtsQLB, and FtsLWI using AlphaFold2 (AF2) 22 .…”

Section: Introductionmentioning

confidence: 99%

Conformational changes in the essentialE. coliseptal cell wall synthesis complex suggest an activation mechanism

Britton

Yovanno

Costa

et al. 2022

Preprint

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The bacterial divisome, a macromolecular machine that is composed of more than thirty proteins in E. coli, orchestrates the essential process of cell wall constriction during cell division. Novel antimicrobial strategies can target protein-protein interactions within the divisome and will benefit from insights into divisome structure and dynamics. In this work, we combined structure prediction, molecular dynamics simulation, single-molecule imaging, and mutagenesis to construct a model of the core complex of the E. coli divisome composed of the essential septal cell wall synthase complex formed by FtsW and FtsI, and its regulators FtsQ, FtsL, FtsB, and FtsN. We observed extensive interactions in four key regions in the periplasmic domains of the complex. FtsQ, FtsL, and FtsB scaffold FtsI in an extended conformation with the FtsI transpeptidase domain lifted away from the membrane through interactions among the C-terminal domains. FtsN binds between FtsI and FtsL in a region rich in residues with superfission (activating) and dominant negative (inhibitory) mutations. Mutagenesis experiments in cellulo and in silico revealed that the essential domain of FtsN functions as a tether to tie FtsI and FtsL together, impacting interactions between the anchor-loop of FtsI and the putative catalytic region of FtsW, suggesting a mechanism of how FtsN activates the cell wall synthesis activities of FtsW and FtsI.

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An Updated Model of the Divisome: Regulation of the Septal Peptidoglycan Synthesis Machinery by the Divisome

Cited by 25 publications

References 127 publications

A model of the interactions between the FtsQLB and the FtsWI peptidoglycan synthase complex in bacterial cell division

A model of the interactions between the FtsQLB and the FtsWI peptidoglycan synthase complex in bacterial cell division

Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

Conformational changes in the essentialE. coliseptal cell wall synthesis complex suggest an activation mechanism

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