NDLI: The structural assembly switch of cell division protein FtsZ probed with fluorescent allosteric inhibitors

Content Provider	Royal Society of Chemistry (RSC)
Author	López-Rodríguez, María L. Chacón, Pablo Vázquez-Villa, Henar Huecas, Sonia Martín-Galiano, A. Javier Araujo-Bazán, Lidia Martín-Fontecha, Mar Andreu, José M. Artola, Marta Oliva, María A. Ramírez-Aportela, Erney Ruíz-Avila, Laura B. Martínez, R. Fernando
Copyright Year	2017
Abstract	FtsZ is a widely conserved tubulin-like GTPase that directs bacterial cell division and a new target for antibiotic discovery. This protein assembly machine cooperatively polymerizes forming single-stranded filaments, by means of self-switching between inactive and actively associating monomer conformations. The structural switch mechanism was proposed to involve a movement of the C-terminal and N-terminal FtsZ domains, opening a cleft between them, allosterically coupled to the formation of a tight association interface between consecutive subunits along the filament. The effective antibacterial benzamide PC190723 binds into the open interdomain cleft and stabilizes FtsZ filaments, thus impairing correct formation of the FtsZ ring for cell division. We have designed fluorescent analogs of PC190723 to probe the FtsZ structural assembly switch. Among them, nitrobenzoxadiazole probes specifically bind to assembled FtsZ rather than to monomers. Probes with several spacer lengths between the fluorophore and benzamide moieties suggest a binding site extension along the interdomain cleft. These probes label FtsZ rings of live Bacillus subtilis and Staphylococcus aureus, without apparently modifying normal cell morphology and growth, but at high concentrations they induce impaired bacterial division phenotypes typical of benzamide antibacterials. During the FtsZ assembly–disassembly process, the fluorescence anisotropy of the probes changes upon binding and dissociating from FtsZ, thus reporting open and closed FtsZ interdomain clefts. Our results demonstrate the structural mechanism of the FtsZ assembly switch, and suggest that the probes bind into the open clefts in cellular FtsZ polymers preferably to unassembled FtsZ in the bacterial cytosol.
Starting Page	1525
Ending Page	1534
Page Count	10
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	8
Issue Number	2
Journal	Chemical Science
DOI	10.1039/c6sc03792e
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Cell division Fluorescence Benzamide Cytosol Protein C-terminus N-terminus FtsZ Antibiotics Fluorophore Aureus Anisotropy Bacillus Monomer GTPase
Content Type	Text
Resource Type	Article
Subject	Chemistry

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sembly switch of cell division protein FtsZ probed with fl uorescent allosteric inhibitors

Mapping Flexibility and the Assembly Switch of Cell Division Protein FtsZ by Computational and Mutational Approaches

Assembly dynamics of FtsZ rings in Bacillus subtilis and Escherichia coli and effects of FtsZ-regulating proteins (2004)

The Cell Division Protein FtsZ from Streptococcus pneumoniae Exhibits a GTPase Activity Delay

The c-terminal domain of minc inhibits assembly of the z ring in escherichia coli - (2006).

The c terminus of ftsz regulates ftsz assembly dynamics and is required for bacillus (2013).

A rapid fluorescence assay for FtsZ assembly indicates cooperative assembly with a dimer nucleus (2005)

Structural Change in FtsZ Induced by Intermolecular Interactions between Bound GTP and the T7 Loop

Mutations in the bacterial cell division protein FtsZ highlight the role of GTP binding and longitudinal subunit interactions in assembly and function

The structural assembly switch of cell division protein FtsZ probed with fluorescent allosteric inhibitors

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sembly switch of cell division protein FtsZ probed with fl uorescent allosteric inhibitors

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Assembly dynamics of FtsZ rings in Bacillus subtilis and Escherichia coli and effects of FtsZ-regulating proteins (2004)

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The c-terminal domain of minc inhibits assembly of the z ring in escherichia coli - (2006).

The c terminus of ftsz regulates ftsz assembly dynamics and is required for bacillus (2013).

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Structural Change in FtsZ Induced by Intermolecular Interactions between Bound GTP and the T7 Loop

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The structural assembly switch of cell division protein FtsZ probed with fluorescent allosteric inhibitors